Imidazopyridine derivatives as kinase inhibitors

ABSTRACT

A compound of the formula 
                         
and physiologically acceptable salts and or N-oxides thereof wherein,
     X 1  is N or CR 3 ; X 2  is N or CR 4 ; X 3  is N or CR 5 ; X 4  is N or CR 6 .   with the proviso that at least one but not more than two of X 1 , X 2 , X 3  and X 4  represents N.   R 1  is a 5-, or 6-membered heterocyclic group selected from group a, b, c or d   
                         
wherein X 5  is a group selected from N or CR 7  and X 6  is a group selected from O, S or NR 8 ; X 7  and X 8  which may be the same or different is a group selected from N or CR 9 ; X 9  is a group selected from O, S or NR 8  and X 10  is N or CR 10 ; X 11 , X 12  and X 13  may be the same or different and selected from a group N or CR 11 ; processes for their preparation, pharmaceutical compositions containing them and their use in medicine.

The present invention relates to novel imidazopyridine derivatives, toprocesses for their preparation, to pharmaceutical compositionscontaining them and to their use in medicine. More particularly thepresent invention relates to novel imidazopyridine derivatives which areinhibitors, of kinases and in particular of mitogen and stress activatedprotein kinase-1 (herein after referred to as Msk-1) and or Rho-kinase 1and or 2 (herein after referred to as ROCK 1 and 2).

An important mechanism by which cells sense and respond to extracellularstimuli is the activation and modulation of intracellular signaltransduction pathways. One of the major signal transduction systemsutilized by cells is the MAPK signalling pathways. These pathways sharea common architecture, consisting of a cascade of protein kinases thatare sequentially phosphorylated and activated, resulting in theactivation of a MAP kinase (MAPK). Three MAP kinase pathways have beenwidely characterised: the Erk pathway, which responds to mitogenicstimuli and results in activation of Erk, and the JNK and p38 pathways,which are commonly associated with transducing cellular stress signalsand result in activation of JNK and p38 MAPK.

Mitogen and stress-activated protein kinases 1 (Msk1) and 2 (Msk2, alsonamed RSKB or RLPK) constitute a family of kinases that can bephosphorylated and activated by either p38 or Erk. Msks are reported tobe localized exclusively to the nucleus, and are responsible for thephosphorylation and activation of the transcription factor CREB inresponse to certain stress stimuli. In macrophage and monocyte cells,Msk1 is involved in CREB-mediated transcriptional regulation of IL-1βand Cox2 in response to bacterial lipopolysaccharide. In addition, Msk1can also phosphorylate the nucleosomal proteins histone H3 and HMG14,and thus may have a critical role in linking cellular signallingpathways to chromatin modification and modulation of transcriptionfactor complexes. Inhibitors of kinases in the Erk MAPK cascade havebeen suggested for use in the treatment and/or prophylaxis of disordersassociated with neuronal degeneration resulting from ischemic events,including cerebral ischemia after cardiac arrest, stroke andmulti-infarct dementia and also after cerebral ischemic events such asthose resulting from head injury, surgery and/or during childbirth.Since Msks are activated by Erk MAPK, Msk inhibitors could serve asimilar use. Although Msks are only one of a number of Erk substrates,CREB is involved in many different transcriptional activities, andMsk-mediated CREB phosphorylation could play a role in some cancers. Inaddition, through modulation of production of pro-inflammatory cytokinessuch as IL-1β and prostaglandins, inhibitors of Msks could be of use intreatments for neuroinflammatory diseases such as stroke, multiplesclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis and inflammatory pain, as well as other inflammatory diseasessuch as rheumatoid arthritis, irritable bowel syndrome, inflammatorybowel disease and asthma.

Another of the major signal transduction systems utilized by cells isthe RhoA-signalling pathways. RhoA is a small GTP binding protein thatcan be activated by several extracellular stimuli such as growth factor,hormones, mechanic stress, osmotic change as well as high concentrationof metabolite like glucose. RhoA activation involves GTP binding,conformation alteration, post-translational modification(geranylgeranyllization and farnesylation) and activation of itsintrinsic GTPase activity. Activated RhoA is capable of interacting withseveral effector proteins including ROCKs and transmit signals intocellular cytoplasm and nucleus.

ROCK1 and 2 constitute a family of kinases that can be activated byRhoA-GTP complex via physical association. Activated ROCKs phosphorylatea number of substrates and play important roles in pivotal cellularfunctions. The substrates for ROCKs include myosin binding subunit ofmyosin light chain phosphatase (MBS, also named MYPT1), adducin, moesin,myosin light chain (MLC), LIM kinase as well as transcription factorFHL. The phosphorylation of theses substrates modulate the biologicalactivity of the proteins and thus provide a means to alter cell'sresponse to external stimuli. One well documented example is theparticipation of ROCK in smooth muscle contraction. Upon stimulation byphenylephrine, smooth muscle from blood vessels contracts. Studies haveshown that phenylephrine stimulates b-adrenergic receptors and leads tothe activation of RhoA. Activated RhoA in turn stimulates kinaseactivity of ROCK1 and which in turn phosphorylates MBS. Suchphosphorylation inhibits the enzyme activity of myosin light chainphosphatase and increases the phosphorylation of myosin light chainitself by a calcium-dependent myosin light chain kinase (MLCK) andconsequently increases the contractility of myosin-actin bundle, leadingto smooth muscle contraction. This phenomena is also sometimes calledcalcium sensitization. In addition to smooth muscle contraction, ROCKshave also been shown to be involved in cellular functions includingapoptosis, cell migration, transcriptional activation, fibrosis,cytokinesis, inflammation and cell proliferation. Moreover, in neuronsROCK plays a critical role in the inhibition of axonal growth bymyelin-associated inhibitory factors such as myelin-associatedglycoprotein (MAG). ROCK-activity also mediates the collapse of growthcones in developing neurons. Both processes are thought to be mediatedby ROCK-induced phosphorylation of substrates such as LIM kinase andmyosin light chain phosphatase, resulting in increased contractility ofthe neuronal actin-myosin system.

Inhibitors of ROCKs have been suggested for use in the treatments of avariety of diseases. They include cardiovascular diseases such ashypertension, chronic and congestive heart failure, cardiac hypertrophy,restenosis, chronic renal failure and atherosclerosis. In addition,because of its muscle relaxing properties, it is also suitable forasthma, male erectile dysfunctions, female sexual dysfunction andover-active bladder syndrome. ROCK inhibitors have been shown to possessanti-inflammatory properties. Thus they can be used as treatment forneuroinflammatory diseases such as stroke, multiple sclerosis,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosisand inflammatory pain, as well as other inflammatory diseases such asrheumatoid arthritis, irritable bowel syndrome, inflammatory boweldisease. In addition, based on their neurite outgrowth inducing effects,ROCK inhibitors could be useful drugs for neuronal regeneration,inducing new axonal growth and axonal rewiring across lesions within theCNS. ROCK inhibitors are therefore likely to be useful for regenerative(recovery) treatment of CNS disorders such as spinal cord injury, acuteneuronal injury (stroke, traumatic brain injury), Parkinsons disease,Alzheimers disease and other neurodegenerative disorders. Since ROCKinhibitors reduce cell proliferation and cell migration, they could beuseful in treating cancer and tumor metastasis. Further more, there isevidence suggesting that ROCK inhibitors suppress cytoskeletalrearrangement upon virus invasion, thus they also have potentialtherapeutic value in anti-viral and anti-bacterial applications. ROCKinhibitors are also useful for the treatment of insulin resistance anddiabetes.

WO 97/12615 teaches novel 2-heteroaryl benzimidazole derivatives, whichare inhibitors of the specific lipoxygenase enzyme 15-LO.

We have now identified a group of novel imidazopyridine derivativeswhich are potent inhibitors of the protein kinase Msk-1 and orRho-associated kinase 1 and or 2.

The present invention thus provides compounds of the general formula (I)

and physiologically acceptable salts and or N-oxides thereof wherein,

-   X₁ is N or CR₃; X₂ is N or CR₄; X₃ is N or CRC; X₄ is N or CR₆.-   with the proviso that at least one but not more than two of X₁, X₂,    X₃ and X₄ represents N.-   R₁ is a 5-, or 6-membered heterocyclic group selected from group a,    b, c or d

wherein X₅ is a group selected from N or CR₇ and X₆ is a group selectedfrom O, S or NR₈;

wherein X₇ and X₈ which may be the same or different is a group selectedfrom N or CR₉;

wherein X₉ is a group selected from O, S or NR₈ and X₉ is N or CR₁₀;

wherein X₁₁, X₁₂ and X₁₃ may be the same or different and selected froma group N or CR₁₁;

R₂ and R₈ independently represents hydrogen, hydroxy, aryl, heteroaryl,C₃₋₇cycloalkyl, heterocyclyl, a group YR₁₂, N═R₁₃, CONR₁₄R₁₅,COCH₂NR₁₉R₂₀, NR₁₄COR₁₆, SO₂NR₁₄R₁₅ or C₁₋₆alkyl [optionally substitutedby a group selected from optionally substituted phenyl, C₃₋₇cycloalkyl,heteroaryl, heterocyclyl, acylamino, NH₂, R₁₉NH, R₁₉R₂₀N, SO₂NR₁₄R₁₅,CONR₁₄R₁₅, NR₁₄COR₁₆, OalkNR₁₉R₂₀, SalkNR₁₉R₂₀ or NR₁₇SO₂R₁₈ group];

R₃, R₄, R₅, R₆, R₇, R₉, R₁₀ and R₁₁ independently represent a groupselected from hydrogen, halogen, hydroxy, R₁₉O, R₁₉S(O)_(n), NH₂, R₁₉NH,R₁₉R₂₀N, nitro, formyl, C₁₋₄alkanoyl, alkenyl (optionally substituted byoptionally substituted phenyl, heterocyclyl, or heteoaryl), carboxy,optionally substituted phenyl, heteroaryl, cycloalkyl, cycloalkylalkyl,aryloxy, heteroaryloxy, heterocyclyl, CONR₁₄R₁₅, NR₁₄COR₁₆, SO₂NR₁₄R₁₅,NR₁₇SO₂R₁₈ or C₁₋₆alkyl [optionally substituted by a group selected fromoptionally substituted phenyl, C₃₋₇cycloalkyl, heteroaryl, heterocyclyl,NH₂, R₁₉NH, R₁₉R₂₀N, acylamino, hydroxy, CONR₁₄R₁₆, NR₁₄COR₁₆,SO₂NR₁₄R₁₅, NR₁₇SO₂R₁₈, OalkNR₁₉R₂₀, or SalkNR₁₉R₂₀ group]; R₁₉ and R₂₀independently represent a group selected from C₁₋₆ alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroarylalkyl, heterocyclyl or heterocyclylalkyl;

Y represents O, NH, NR₁₂ or S(O)_(n);

R₁₂ represents aryl, heteroaryl, cycloalkyl, heterocyclyl or C₁₋₆alkyl[optionally substituted by a group selected from optionally substitutedphenyl, C₃₋₇Cycloalkyl, heteroaryl, heterocyclyl, NH₂, R₁₉NH, R₁₉R₂₀N,acylamino, hydroxy, CONR₁₄R₁₅, NR₁₄COR₁₆, SO₂NR₁₄R₁₅, NR₁₇SO₂R₁₈OalkNR₁₉R₂₀, or SalkNR₁₉R₂₀ group];

R₁₃ represents an alkylidene group which may be substituted by an aryl,heteroaryl, heterocyclyl or cycloalkyl group or R₁₃ represents acycloalkylidene or heterocycloalkylidene group.

R₁₄ and R₁₅ independently represent hydrogen, aryl, heteroaryl,cycloalkyl or C₁₋₆-alkyl [optionally substituted by a group selectedfrom optionally substituted phenyl, C₃₋₇cycloalkyl, heteroaryl,heterocyclyl, NH₂, R₁₉NH, R₁₉R₂₀N, or acylamino group] or R₁₄ and R₁₅together with the nitrogen atom to which they are attached form a 4-7heterocyclic ring which may be saturated or unsaturated and optionallycontains another heteroatom selected from O, N or S(O)_(n);

R₁₆ and R₁₈ independently represent, aryl, heteroaryl, heterocyclyl,cycloalkyl or C₁₋₆alkyl [optionally substituted by a group selected fromoptionally substituted phenyl, C₃₋₇cycloalkyl, heteroaryl, heterocyclyl,NH₂, R₁₉NH, R₁₉R₂₀N, or acylamino group] or the group NR₁₄R₁₅ whereinR₁₄ and R₁₅ have the meanings defined above;

R₁₇ represents hydrogen, aryl, heteroaryl, heterocyclyl, cycloalkyl orC₁₋₆alkyl [optionally substituted by a group selected from optionallysubstituted phenyl, C₃₋₇cycloalkyl, heteroaryl, heterocyclyl, NH₂,R₁₉NH, R₁₉R₂₀N, or acylamino group];

Alk is a C₂₋₄ straight or branched alkylene chain

n is zero, 1 or 2.

It will be appreciated that any of the substituents R₁ to R₂₀ as definedin formula (I) above may contain at least one asymmetric center and itis to be understood that the invention includes all possible enantiomersarising therefrom and mixtures thereof including racemates.

The term alkyl as a group or part of a group e.g. alkoxy, alkylthio,alkylamino, dialkylamino, optionally substituted alkyl e.g. aminoalkyl,cycloalkylalkyl, aralkyl, heteroarylalkyl or heterocyclylalkyl refers toa C₁₋₆ straight or branched chain alkyl group.

The term halogen includes fluorine, chlorine, bromine or iodine.

The term aryl as a group or part of a group e.g. aryloxy, aralkyl orarylamino refers to an optionally substituted phenyl or fused bicyclicaryl group e.g. naphthyl.

The terms aryl, optionally substituted phenyl, heteroaryl, C₃₋₇cycloalkyl as a group or part of a group and 4-7 membered heterocyclylas a group or part of a group includes such groups which are optionallysubstituted with 1 to 3 substituents which may be the same or differentand selected from halogen, aryl, heteroaryl, heterocyclylalkyl, hydroxy,alkyl, alkoxy, trifluoroalkyl, amino, alkylamino, dialkylamino,arylamino, heteroarylamino, heterocyclylamino, acylamino, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, arylaminoalkyl,heteroarylaminoalkyl, cycloalkylaminoalkyl, heteroclylaminoalkyl,hydroxyalkyl, CONR₁₄R₁₅, CH2CONR₁₄R₁₅ carboxy, carboxamido,alkoxycarbonyl, aminoalkoxy, dialkylaminoalkoxy, acylaminoalkoxy,sulphonamido, aminosulphonyl, cyano, formyl, nitro, R₂₁O or R₂₁S(O)_(n)wherein R₂₁ is a group selected from alkyl, aryl, heteroaryl orheterocyclylalkoxy and n is zero, one or two, or each of the said groupsform part of a fused bicyclic ring system containing up to 10 ringmembers and which is at least partially saturated.

The term heteroaryl as a group or part of a group e.g. heteroaryloxyrefers to a 5, or 6 membered ring or a fused 5,6 or 6,6 bicyclic ringsystem.

When heteroaryl represents a 5 membered group it contains a heteroatomselected from O, N or S and may optionally contain a further 1 to 3nitrogen atoms. Examples of such groups include furanyl, thienyl,isoxazolyl, oxazolyl or imidazolyl.

When heteroaryl represents a 6-membered group it contains from 1 to 3nitrogen atoms. Examples of such groups include pyridyl, pyrimidinyl, ortriazinyl.

The term 5,6 fused bicyclic heteroaryl group refers to a group in whichthe 5-membered ring contains an oxygen, sulphur or NH group and the 6membered ring optionally contains from 1 to 3 nitrogen atoms. Examplesof such groups include benzofuranyl, benzothienyl or indolyl.

The term 6,6-fused bicyclic heteroaryl group refers to a bicyclicheteroaryl group which contains at least one nitrogen atom in one of therings and may contain up to 3 nitrogen atoms in each ring. Examples ofsuch groups include quinolinyl, isoquinolinyl or naphthyridinyl also theterm 6,6 fused bicyclic heteroaryl group refers to a 6-memberedheteroaryl group which is fused to a partially saturated carbocyclicgroup. Examples of such a group includes tetrahydroquinolinyl ortetrahydroisoquinolinyl.

The term heterocyclyl as a group or part of a group e.g.heterocyclylalkyl or heterocyclylalkylidene refers to a bridgedheterocyclic group or a 4-7 membered heterocyclyl group which is linkedto the rest of the compound of formula (I) via a carbon or nitrogen atomin that group and which contains one or two hetero atoms selected fromN, O or S(O)_(n), and when the heterocyclyl group contains a ring memberNH or the heterocyclyl group is substituted by a primary or secondaryamino group then the term also includes N-alkyl, N-optionallysubstituted phenyl, N-benzyl or, N-acyl derivatives thereof. The termheterocyclic also includes bridged heterocyclic. Examples of suchheterocyclic groups include optionally substituted pyrrolidine,piperidine, piperazine homopiperazine, morpholine, thiomorpholine and(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine.

The term cycloalkyl as a group or part of a group e.g. cycloalkylalkylor cycloalkylidene refers to a 3-7 membered carbocyclic group.

The term fused bicyclic ring system containing up to 11 ring members andwhich is at least partially saturated includes carbocyclic andheterocyclic 6,5,6,6 and 6,7 bicyclic ring systems. Examples of such 6,5and 6,6 carbocyclic ring systems include those wherein the bicyclic ringcomprises a benzene ring fused to a 5-, 6- or -membered carbocyclic ringwhich is at least partially saturated e.g. tetrahydronaphthyl, indanylor indenyl. Examples of such 6,5, 6,6 or 6,7 heterocyclic rings includethose wherein one ring is benzene which is fused to a 5, 6 or 7 memberedring containing one or two hetero atoms selected from O, S or N e.g.indolinyl, isoindolinyl, 2,3-dihydro-1H-isoindol-5-yl,dihydrobenzofuranyl, dihydrobenzothienyl, 1,3-benzodioxolyl,benzopyrrolyl, 1,3-benozodithiolyl, 1,4-benzodioxanyl, chromanyl,chromenyl or 2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl.

The term acyl as a group or part of the acylamino group referes to analkanoyl, aroyl, aralkanoyl, alkoxycarbonyl, aryloxycaronyl oraralkoxycarbonyl group.

The compounds of formula (I) form salts with inorganic and organic acidsand the invention includes such salts formed with physiologicallyacceptable inorganic and organic acids.

The compounds of formula (I), form N-oxides. Thus, the compound offormula (I) wherein X₃ is N or X₂ is N forms an N oxide and theinvention includes such compounds.

A preferred class of compounds of formula (I) are those wherein only oneof X₁, X₂, X₃ or X₄ represents N. Within this class conveniently X₂ orX₃ represent N or more particularly X₃ represents N.

A further preferred class of compounds are those wherein X₁ and X₃ eachrepresents N.

A further preferred class of compounds of formula (I) are those whereinR₁ is a group selected from (c) or (d).

A prefered group of compounds according to the invention are those offormula (I) wherein X₃ is N, X₁ is CR₃; X₂ is CR₄ and X₄ is CR₆.

R₁ is a group c wherein X₉ is O and X₁₀ is N; Within this group apreferred class are those wherein R₂ is hydrogen, optionally substitutedalkyl, aryl, heteroaryl, C3-7cycloalkyl or heterocyclyl,

R₃ represent a group selected from hydrogen, halogen, R₁₉O, R₁₉S(O)_(n),R₁₉NH, R₁₉R₂₀N, carboxyl,)CONR₁₄R₁₅, SO₂NR₁₄R₁₅, optionally substitutedphenyl, heteroaryl, C₁₋₆alkyl, or methyl [substituted by a groupselected from optionally substituted phenyl, R₁₉NH, R₁₉R₂₀N, CONR₁₄R₁₅,SO₂NR₁₄R₁₅R₁₉O or R₁₉S(O)_(n) R₄ represents hydrogen, halogen,optionally substituted C₁₋₄alkyl, R₁₉O, R₁₉S(O)_(n), R₁₉NH or R₁₉R₂₀N;R₆ represents hydrogen, halogen, optionally substituted C₁₋₆-alkyl,optionally substituted phenyl, R₁₉NH, R₁₉R₂₀N, R₁₉O or R₁₉S(O)_(n) ormethyl substituted by optionally substituted phenyl.

When R₁ is the group (c) this is conveniently a group wherein X₉ isoxygen and X₁₀ is nitrogen or X₉ is NR₈ wherein R₈ is hydrogen or methyland X₉ is CH.

When R₁ is the group (d) this is conveniently a group wherein X₁, andX₁₂ each represent CH and X₁₃ is the group CH or N.

The group R₁ is preferably a group (c) wherein X₉ is oxygen and X₁₀ isnitrogen.

Examples of suitable R₂ groups include hydrogen, C₁₋₆alkyl such asmethyl, ethyl, isopropyl, sec butyl and 2-ethylbutyl, C₃₋₇ cycloalkyle.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,C₃₋₇cycloalkylalkyl e.g. C₃₋₇ cycloalkylmethyl such as cyclopropylmethylor cyclohexylmethyl, optionally substituted phenyl such as phenyl orphenyl substituted by [amino eg 4-aminophenyl, dialkylamino, egdimethylamino, dialkylaminoalkylamino (eg dimethylaminoethylamino,N-methyl, dimethylaminoethylamino, N,N-bis(2-dimethylaminoethyl)amino),alkyl eg ethyl, alkanoyl eg acetyl, alkoxy (eg methoxy or3-methylbutoxy)halo, (eg chlorine or bromine, hydroxy, aminoalkyl egaminomethyl, hydroxalkoxy (eg 2-hydroxyethoxy or 3-hydroxypropoxy),aminoalkoxy eg 2-aminoethoxy, alkylaminoalkoxy eg 2-methylaminoethoxy,dialkylaminoethoxy (eg 2-dimethylaminoethoxy, 2 diethylaminoethoxy, 2diethylamino-1-methylethoxy, 2-disopropylamino-1-methylethoxy),N-aralkyl-Nalkylaminoalkoxy eg N-benzyl N-methylaminoethoxy,aminocarbonylalkoxy eg (aminocarbonylmethoxy,aminocarbonyl-2-methylethoxy, aminocarbonylethoxy),alkylaminocarbonylalkoxy eg methylaminocarbonylmethoxy,dialkylaminocarbonylalkoxy, eg dimethylaminocarboxymethoxy, ureidoalkoxyeg ureidomethoxy, alkylureido eg 3-methylureido, dialkylamino-acetamidoeg dimethylaminoacetamido, alky(thioalkoxy eg methylthiomethoxy,phenylthioalkoxy eg phenylthiomethoxy, alkisulphinylalkoxy egmethylsulphinylmethoxy, phenylsulphinylalkoxy eg phenylsulphinylmethoxy,alkylsulphonylalkoxy eg methylsulphonylmethoxy, phenylsulphonylalkoxy egphenylsulphonylmethoxy, cyanoalkoxy eg cyanomethoxy or 2-cyanoethoxy,acylaminoethoxy eg (t-butoxycarbonylaminoethoxy, isoxazolylaminoethoxy,isonicotinylaminoethoxy, alkylsuphonylamino-alkoxy egmethylsulphonylaminoethoxy, phenylsulphonylaminoalkoxy egphenylsulphonylaminoethoxy, alkoxycarbonylalkoxy eg 2-methoxycarbonyl1-methylethoxy, heterocyclylalkoxy eg (morpholinoethoxy,piperidinoethoxy, 1-pyrroldino-2-ylmethoxy, heterocyclyloxy e.g.1-methyl-piperidino-4-yloxy, heterocyclyl eg 3-pyrrolidinyl,], alkyl(substituted by hydroxy e.g. 2-hydroxy-1-methyl-ethyl), alkylsubstituted by [amino eg (3-aminopropyl, 4-aminobutyl, 5 aminopentyl),acylamino e.g. 4-butyloxycarbonylamino-butyl, R₁₉NH or R₁₉R₂₀N e.g.(2-dimethylamino-1-methylethyl, 4-diethylamino-1-methyl-butyl or3-dimethylaminopropyl)], alkyl e.g. methyl or ethyl substituted by a4-7-membered heterocyclyl group e.g. 4-methylpiperazin-1-ethyl,2-piperazin-yl-ethyl, piperidine 4-yl methyl or piperidine 3-yl methyl,a 4-7 membered heterocyclyl group such as piperidinyl e.g.piperidin-4-yl or piperidin-3-yl or pyrrolidinyl e.g. pyrrolidin-3-yl, a5,6 fused bicyclic hetroaryl group such as indazolyl e.g. 5-indazolyl or6-indazolyl, or 6,6 fused bicyclicheterocyclic e.g.tetrahydroisoquinolin-5-yl, 2-methyl tetrahydroisoquinolin-7-yl,2-methanesulphonyl-tetrahydroisoquinolin-7-yl ortetrahydroisoquinolin-7-yl, 3,4 dihydro-2H-isoquinolin-1-one-7-yl, a 6,5fused heterocyclic group e.g. 2,3-dihydro-1H-isoindol-5-yl, orbenzo{1,3]dioxol-5-yl or a 6,7 fused heterocyclic e.g.2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl.

When X₂ is CR₄ then the group R₄ is conveniently hydrogen, methyl oralkoxy e.g, methoxy, alkylthio e.g. methylthio, phenylamino or phenoxyoptionally substituted by halogen e.g. fluoro or acetamido.

When X₃ is CR₅ then R₅ is coveniently hydrogen, alkyl e.g. methyl oralkoxy e.g. methoxy or optionally substituted phenoxy e.g. phenoxy.

Wherein X₄ is CR₆ the group R₆ is conveniently hydrogen, halogen e.g.chlorine, hydroxyalkyl e.g hydroxymethyl, alkyl e.g, methyl, alkoxy e.g.methoxy, optionally substituted phenyl e.g. phenyl or a 4-7 memberedheterocyclyl group e.g. 1-pyrrolidinyl or 1-pyrazolyl.

Wherein X₁ is the group CR₃ then R₃ is conveniently hydrogen, halogene.g. bromine, hydroxy, carboxyl, optionally substituted phenyl e.g.phenyl or phenyl (substituted by one or two groups selected from alkoxye.g. methoxy or ethoxy, hydroxy, hydroxymethyl, trifluoromethyl,trifluoromethoxy, amino, acetamido, aminoalkyl, e.g. aminomethyl, oraminoethyl, alkyl e.g. methyl or ethyl, carboxyl carboxamido,N,N-dimethylcarboxamido, cyano, formyl, aryloxy e.g. phenoxy CH₃S(O)_(n)wherein n is zero, 1 or 2, CH₃SO₂NH, or halogen e.g. fluorine), orheterocyclyl e.g. 5-methyl-1,2,4-oxadiazol-3-yl, an heteroaryl group e.gthienyl (optionally substituted by formyl, alkyl eg methyl or phenyl)such as 2-thienyl, 4-methylthienl, 5-phenylthienyl, 5-formylthienyl, or3-thienyl, 2-furanyl, pyridyl such as 3-pyridyl or 4-pyridyl,3,5-dimethylisoxazol-4-yl, indolyl or 8-quinolinyl, benzothienyl, a6,5-fused bicycloheterocyclyl e.g 5-benzo[1,3]dioxolylor R₃ isoptionally substituted phenyl such as phenyl or halophenyl e.g.fluorophenyl substituted by the group CH₂NR₁₉R₂₀ wherein R₁₉ is alkyle.g. methyl or ethyl, phenyl or a heterocyclic group such as a 4-7heterocyclic group and R₂₀ is hydrogen or methyl, or NR₁₉R₂₀ is a 4-7heterocyclic group. Examples of suitable NR₁₉R₂₀ groups includeethylamino, dimethylamino, 4-morpholino, pyrrolidino, piperidino,piperidin-4-yl-amino or 1-t-butoxycarbonyl-piperdin-4-yl-amino, or

-   R₃ is alkyl substituted by a 4-7 membered heterocyclyl group or a    group NR₁₉R₂₀ wherein R₁₉ is hydroxylalkyl, optionally substituted    benzyl, C₃₋₇ cycloalkyl, a heterocyclic group e.g. bridge    heterocycle, or a 4-7 membered heterocyclyl, 4-7 membered    heterocycylalkyl or C₃₋₇ cycloalkylalkyl Conveniently the 4-7    membered heterocyclyl group or moiety is selected from a 5-7    membered group containing one or 2 ring members selected from    nitrogen or oxyen e.g. pyrrolidinyl, piperidinyl, morpholinyl    piperazinyl or homo-piperazinyl. R₂₀ is hydrogen, methyl or acetyl.    Examples of such R₃ groups include 3-hydroxypropylamino,    4-bromobenzylamino, 4-methoxybenzylamino, 4-piperidinylaminomethyl,    N4-piperidinyl-N-methylaminomethyl,    1-t-butyoxycarbonyl-piperidinyl-aminomethyl 4-aminopiperidinomethyl,    1,4-diazepan-1-ylmethyl, piperazinomethyl, 4-methylpiperazinomethyl,    4-acetylpiperizin-1-ylmethyl, 4-ethylpiperazinomethyl    4-morpholinomethyl, piperidinomethyl,    4-(methylamino)piperidinomethyl, 4-cyclopropylaminopiperidinomethyl,    pyrrolidinomethyl, 3-dimethylaminopyrrolidinomethyl,    2-hydroxymethylpyrrolidinomethyl, 4-ethylpiperazino-methyl,    3-pyrrolidin-1-yl-propylaminomethyl,    4-(4-fluorophenyl)piperazinomethyl,    3-piperidinyl-1-yl-propylaminomethyl,    3-morpholin-4-yl-propylaminomethyl, 3-(4-methylpiperazin-yl    propylaminomethyl, 1-methyl piperidin-4-yl-aminomethyl,    4-pyrrolidinocarbonylmethyl-piperazinomethyl,    2-pyrrolidin-1-ylmethylpyrrolidinomethyl,    2-pyrrolidin-1-yl-ethylaminomethyl,    3-dimethylaminopyrrolidinomethyl,    1-methyl-piperidin-4-ylaminomethyl,    1-isopropyl-piperidin-4-ylaminomethyl,    3-dimethylaminopyrrolidinomethyl,    2-(morpholin-yl-methyl)-pyrrolidinomethyl,    3-piperidin-1-yl-propylaminomethyl,    3-morpholin-4-yl-propylaminomethyl,    3-(4-methylpiperazin-1-ylpropylaminomethyl,    piperidin-1-ylmethylpyrrolidinomethyl, 3,5-dimethylpiperazinomethyl,    pyrrolidin-1-ylpiperidinomethyl, pyrrolidino-3-ylaminomethyl,    pyrrolidin-2-ylmethylaminomethyl,    4-aminomethylcyclohexymethylaminomethyl,    4-aminocyclohexylaminomethyl, 2-piperazin-1-ylethylamoinomethyl,    3-amino-pyrrolidinomethyl, pyrrolidino-2-ylmethylaminomethyl,    piperidin-4-ylmethylaminomethyl, 4-aminomethylpiperdininomethyl,    4-(cyclopropylaminopiperidinomethyl,    3-(piperazino-1-yl)propylaminomethyl,    2-(morpholin-4-ylmethyl)pyrrolidinomethyl    2-(piperidin-1-ylmethyl)pyrrolidinomethyl,    2-(piperazin-1-ylmethyl)pyrrolidinomethyl, piperidin-4-ylmethyl,    N-piperidin-4-yl-acetamidomethyl,-   or R₃ is 4-heterocyclyoxy e.g. piperidin-4-yloxy, or    heterocyclylalkyloxy e.g. piperidin-4-ylmethyloxy, or-   R₃ is vinyl optionally substituted by optionally substituted phenyl    e.g. 4-methyloxystyryl or R₃ is the group CONR₁₄R₁₅-   wherein R₁₅ is hydrogen, R₁₄ is benzyl, phenethyl, aminoalkyl e.g.    3-aminopropyl 4-aminobutyl or 6-aminohexyl or is a 4-7 membered    heterocyclyl group. Conveniently the heterocyclyl group is a 5-6    membered group in which one ring member is nitrogen which may be    sustitute by an aminoalkylcarbonyl group. Suitable examples include    piperidinyl e.g. 3 or 4-piperidinyl    1-aminomethylcarbonyl-piperidin-4-yl, or pyrrolidinyl e.g.    3-pyrroldinyl or R₁₄ is a 4-7 membered heterocyclylalkyl group.    Conveniently the heterocyclic moiety is a 5-7 membered group    containing a nitrogen atom and another hetero member selected from    oxygen or nitrogen. Suitable examples of such heterocyclylalkyl    groups include piperidinylmethyl e.g. piperidin-2-ylmethyl or    piperidin-4-ylmethyl, morpholinylmethyl e.g. morpholin-2-ylmethyl or    piperazinoethyl, or R₁₄ and R₁₅ together with the nitrogen atom to    which they are attached represent a 4-7 membered heterocyclyl group.    Conveniently the heterocyclyl group is a 5-7 membered group which    may contain an additional hetero member selected from oxygen,    nitrogen or substituted nitrogen Examples of such groups include    piperazino, 1-methylpiperazino, 4-(2-aminoethyl)piperazino,    4-(t-butoxycarbonylaminoethyl)piperazino,    4-aminoalkylcarbonylpiperazino, e.g.    4-aminomethylcarbonylpiperazino, 4-aminoethylcarbonylpiperazino,    4-1-(aminoethylcarbonylpiperazino,    4-(1-methylaminoethylylcarbonylpiperazino,    4-pyrrolidin-2-yl-carbonylpiperazino, pyrrolidino,    3-aminopyrrolidino, 2-methoxycarbonylpyrrolidino, morpholino,    2-(pyrrolidin-1-yl)methyl pyrrolidino or R₃ is a group R₁₉S(O)_(n)    wherein n is zero, 1 or 2 and R₁₉ is optionally substitued phenyl eg    phenyl optionally substituted by methoxy or heteroaryl and    conveniently n is zero, or R₃ is a group R₁₉NH and R₁₉ is optionally    substitued phenyl or heteroaryl e.g. phenyl, 4-morpholinophenyl or    3-aminopyridyl. Examples of suitable compounds according to the    invention include those whose preparation is specifically described    in examples 1 to 316.

Specific preferred compounds according to the invention include:

-   2-(4-amino-furazan-3-yl)-1-ethyl-N-[(2R)-2-morpholinylmethyl]-1H-imidazo[4,5-c]pyridine-7-carboxamide-   2-(4-amino-furazan-3-yl)-1-ethyl-N-[(2S)-2-morpholinylmethyl]-1H-imidazo[4,5-c]pyridine-7-carboxamide-   4-{6-[(4-fluorophenyl)oxy]-1-[4-(methyloxy)phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine    hydrochloride-   4-{1-(4-{[2-(dimethylamino)ethyl]oxy}phenyl)-6-[(4-fluorophenyl)oxy]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine    hydrochloride-   2-(4-amino-furazan-3-yl)-1-(cyclopropylmethyl)-N-(2-morpholinylmethyl)-1H-imidazo[4,5-c]pyridine-7-carboxamide    hydrochloride-   4-[1-ethyl-6-(methyloxy)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   4-[1-ethyl-6-(methylthio)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   4-[1-ethyl-6-(phenyloxy)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   4-{1-ethyl-6-[(4-fluorophenyl)oxy]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine-   N-(3-{[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5c]pyridin-6-yl]oxy}phenyl)acetamide    hydrochloride-   N-(4-{[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-6-yl]oxy}phenyl)acetamide    hydrochloride-   2-(4-amino-furazan-3-yl)-1-ethyl-N-phenyl-1H-imidazo[4,5-c]pyridin-6-amine-   4-[1-(phenylmethyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine    hydrochloride-   4-[1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   4-[1-(4-fluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-amine    hydrochloride-   4-(6-bromo-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine-   4-{7-bromo-1-[4-(methyloxy)phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine-   4-[2-(4-amino-furazan-3-yl)-7-bromo-1H-imidazo[4,5-c]pyridin-1-yl]phenol-   4-[1-(4-{[2-(dimethylamino)ethyl]oxy}phenyl)-7-phenyl-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   4-(7-bromo-1-phenyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine-   4-(1,7-diphenyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine-   4-[1-phenyl-7-(2-thienyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   4-[2-(4-amino-furazan-3-yl)-1-phenyl-1H-imidazo[4,5-c]pyridin-7-yl]phenol-   2-(4-amino-furazan-3-yl)-1-phenyl-1H-imidazo[4,5-c]pyridine-7-carboxylic    acid-   4-(7-{4-[(ethylamino)methyl]phenyl}-1-phenyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine-   4-[7-(3,5-dimethyl-4-isoxazolyl)-1-phenyl-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   4-{1-ethyl-7-[3-(ethyloxy)phenyl]-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine    hydrochloride-   2-(4-amino-furazan-3-yl)-1-ethyl-N-methyl-1H-imidazo[4,5-c]pyridine-7-sulfonamide    hydrochloride-   2-(4-amino-furazan-3-yl)-1-ethyl-N,N-dimethyl-1H-imidazo[4,5-c]pyridine-7-sulfonamide    hydrochloride-   {3-[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]phenyl}methanol    hydrochloride-   4-(1-ethyl-7-{4-[(phenylamino)methyl]phenyl}-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine-   4-[1-ethyl-7-(2-fluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine    hydrochloride-   4-{1-ethyl-7-[4-(methylsulfonyl)phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine    hydrochloride-   4-{1-ethyl-7-[4-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}furazan-3-ylamine    hydrochloride-   4-[7-(2,4-difluorophenyl)-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine    hydrochloride-   5-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-thiophen-2-yl}-carbaldehyde-   4-[7-(1-benzothien-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine    hydrochloride-   4-{1-ethyl-7-[2-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}furazan-3-ylamine    hydrochloride-   4-{1-ethyl-7-[4-(methylthio)phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine    hydrochloride-   4-[1-ethyl-7-(4-methyl-2-thienyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine    hydrochloride-   4-[7-(2,6-dimethylphenyl)-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine    hydrochloride-   5-[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-2-fluorobenzaldehyde    hydrochloride-   4-[7-(3-aminophenyl)-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine    hydrochloride-   4-(1-ethyl-7-{3-[(trifluoromethyl)oxy]phenyl}-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine    hydrochloride-   1-{3-[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]phenyl}ethanone    hydrochloride-   N-4-[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]phenyl}methanesulfonamide    hydrochloride-   4-[1-ethyl-7-(5-phenyl-2-thienyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine    hydrochloride-   4-{7-[3,5-bis(trifluoromethyl)phenyl]-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine    hydrochloride-   4-{1-ethyl-7-[4-fluoro-3-(1-pyrrolidinylmethyl)phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine    hydrochloride-   4-{1-ethyl-7-[3-fluoro-4-(1-pyrrolidinylmethyl)phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine    hydrochloride-   4-(1-ethyl-7-{4-[(ethylamino)methyl]-3-fluorophenyl}-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine    hydrochloride-   4-(7-{[(3S)-3-amino-1-pyrrolidinyl]sulfonyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine    hydrochloride-   4-{1-ethyl-7-[4-(methylsulfinyl)phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-yl-amine    hydrochloride-   4-[1-ethyl-7-(4-morpholinylcarbonyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   2-(4-amino-furazan-3-yl)-1-ethyl-N-(2-hydroxyethyl)-1H-imidazo[4,5-c]pyridine-7-carboxamide-   4-[1-ethyl-7-(1-piperidinylcarbonyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   2-(4-amino-furazan-3-yl)-1-ethyl-N,N-dimethyl-1H-imidazo[4,5-c]pyridine-7-carboxamide-   2-(4-amino-furazan-3-yl)-1-ethyl-N-(1-methylethyl)-1H-imidazo[4,5-c]pyridine-7-carboxamide-   2-(4-amino-furazan-3-yl)-1-ethyl-N-phenyl-1H-imidazo[4,5-c]pyridine-7-carboxamide-   2-(4-amino-furazan-3-yl)-1-ethyl-N-methyl-1H-imidazo[4,5-c]pyridine-7-carboxamide-   2-(4-amino-furazan-3-yl)-1-ethyl-N-[2-(methyloxy)ethyl]1H-imidazo[4,5-c]pyridine-7-carboxamide-   2-(4-amino-furazan-3-yl)-1-ethyl-N-(2,2,6,6-tetramethyl-4-piperidinyl)-1H-imidazo[4,5-c]pyridine-7-carboxamide-   1,1-dimethylethyl[5-({[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]carbonyl}amino)pentyl]carbamate-   1,1-dimethylethyl    4-{2-[({[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]carbonyl}amino)methyl]phenyl}-1-piperazinecarboxylate-   2-(4-amino-furazan-3-yl)-N-[3-(dimethylamino)propyl]-1-ethyl-1H-imidazo[4,5-c]pyridine-7-carboxamide-   2-(4-amino-furazan-3-yl)-1-ethyl-N-methyl-N-(phenylmethyl)-1H-imidazo[4,5-c]pyridine-7-carboxamide-   2-(4-amino-furazan-3-yl)-1-ethyl-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-1H-imidazo[4,5-c]pyridine-7-carboxamide-   2-(4-amino-furazan-3-yl)-N-[2-(4-chlorophenyl)-1-(hydroxymethyl)ethyl]-1-ethyl-1H-imidazo[4,5-c]pyridine-7-carboxamide-   4-(1-ethyl-7-{[4-(phenylmethyl)-1-piperazinyl]carbonyl}-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine-   2-(4-amino-furazan-3-yl)-1-ethyl-N-{[4-(methyloxy)phenylmethyl)-1H-imidazo[4,5-c]pyridine-7-carboxamide-   2-(4-amino-furazan-3-yl)-N-(5-aminopentyl)-1-ethyl-1H-imidazo[4,5-c]pyridine-7-carboxamide    trifluoroacetate-   2-(4-amino-furazan-3-yl)-1-ethyl-N-((2-(1-piperazinyl)phenyl]methyl}-1H-imidazo[4,5-c]pyridine-7-carboxamide    trifluoroacetate-   2-(4-amino-furazan-3-yl)-N-[(1S,5R,7S)-3-aminotricyclo[3.3.1.1˜3,7-]dec-1-yl]-1-ethyl-1H-imidazo[4,5-c]pyridine-7-carboxamide    trifluoroacetate-   2-(4-amino-furazan-3-yl)-N-{[4-chloro-3-(trifluoromethylphenyl]methyl}-1-ethyl-1H-imidazo[4,5-c]pyridine-7-carboxamide-   4-(1-ethyl-7-{[4-(4-pyridinylmethyl)-1-piperazinyl]carbonyl}-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine-   2-(4-amino-furazan-3-yl)-1-ethyl-N-[2-(4-methyl-1-piperidinyl)ethyl]-1H-imidazo[4,5-c]pyridine-7-carboxamide-   2-(4-amino-furazan-3-yl)-1-ethyl-N-{2-[(phenylmethyl)amino]ethyl}-1H-imidazo[4,5-c]pyridine-7-carboxamide-   4-{1-ethyl-7-[(4-ethyl-1-piperazinyl)carbonyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine-   2-(4-amino-furazan-3-yl)-N-[2-(2,4-dichlorophenyl)ethyl]-1-ethyl-1H-imidazo[4,5-c]pyridine-7-carboxamide-   2-(4-amino-furazan-3-yl)-1-ethyl-N-[2-(methylamino)ethyl]-1H-imidazo[4,5-c]pyridine-7-carboxamide-   4-{1-ethyl-7-[4-(4-morpholinylcarbonyl)phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine-   4-[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-N-(2-phenylethyl)benzamide-   4-{1-ethyl-7-[4-(1-pyrrolidinylcarbonyl)phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine-   4-[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-N-(phenylmethyl)benzamide-   methyl    1-({4-[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]phenyl}carbonyl)-L-prolinate-   4-(1-ethyl-7-{4-[(4-methyl-1-piperazinyl)carbonyl]phenyl})-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine-   3-[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-N-(2-phenylethyl)benzamide-   3-[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-N-(phenylmethyl)benzamide-   methyl    1-({3-[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]phenyl}carbonyl)-L-prolinate-   4-(1-ethyl-7-{3-[(4-methyl-1-piperazinyl)carbonyl]phenyl}-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine-   4-{1-ethyl-7-[3-(4-morpholinylcarbonyl)phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine-   4-[1-ethyl-7-(1-pyrrolidinylcarbonyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   2-(4-amino-furazan-3-yl)-1-ethyl-N-phenyl-1H-imidazo[4,5-c]pyridin-7-amine-   4-[1-ethyl-4-(ethyloxy)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   4-[1-ethyl-4-(methyloxy)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   1-{[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]methyl}4-piperidinamine    hydrochloride-   [2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]methanol-   N-{[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]methyl}-1-(1-methylethyl)-4-piperidinamine    hydrochloride-   1-{[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]methyl}-N-methyl-4-piperidinamine    hydrochloride-   ((2S)-{[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]methyl}-2-pyrrolidinyl)methanol-   4-(7-{[(3R)-3-(dimethylamino)-1-pyrrolidinyl]methyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine    hydrochloride-   4-(7-{[(3S)-3-(dimethylamino)-1-pyrrolidinyl]methyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine    hydrochloride-   3-({[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]methyl}amino)-1-propanol-   4-[1-ethyl-7-({[2-(1-piperazinyl)ethyl]amino}methyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine    hydrochloride-   2-(4-amino-furazan-3-yl)-1-ethyl-N-[(3R)-3-pyrrolidinyl]-1H-imidazo[4,5-c]pyridine-7-carboxamide    hydrochloride-   2-(4-amino-furazan-3-yl)-1-ethyl-N-[(3S)-3-pyrrolidinyl]-1H-imidazo[4,5-c]pyridine-7-carboxamide    hydrochloride-   N-{[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]methyl}-N-4-piperidinylacetamide    hydrochloride-   4-(7-bromo-1-ethyl-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine-   [2-(4-amino-furazan-3-yl)-7-bromo-1-ethyl-1H-imidazo[4,5-c]pyridin-4-yl]methanol    hydrochloride-   4-[1-ethyl-7-({4-[(methylamino)acetyl]-1-piperazinyl}carbonyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine    hydrochloride-   4-(7-{[4-(aminoacetyl)-1-piperazinyl]carbonyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine    hydrochloride-   4-(7-[{(3-aminopropanoyl)-1-piperazinyl]carbonyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine    hydrochloride-   4-[7-({4-[(2R)-2-aminopropanoyl]-1-piperazinyl}carbonyl)-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl-furazan-3-ylamine    hydrochloride-   4-[7-({4-((2S)-2-aminopropanoyl]-1-piperazinyl}carbonyl)-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine    hydrochloride-   4-[9-cyclopropyl-2-(methylthio)-9H-purin-8-yl]-furazan-3-ylamine-   4-[1-(3-Methoxy-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   3-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenol-   1-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-ethanone    oxime-   4-[1-(2-Methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   4-(1-Benzo[1,3]dioxol-5-yl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine-   7-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one-   4-[1-(2-Methanesulfonyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-N-hydroxy-benzamidine-   4-[1-(2,3,4,5-Tetrahydro-1H-benzo[c]azepin-8-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   4-[1-(1H-Indazol-6-yl)-1H-imidazole[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   4-[1-(1H-Indazol-5-yl)-1H-imidazole[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   4-{1-[4-(2-Diethylamino-ethoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine    hydrochloride-   4-{1-[4-(3-Dimethylamino-propoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine    hydrochloride-   4-{1-[4-((S)-1-Pyrrolidin-2-ylmethoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine-   4-{1-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine    hydrochloride-   N-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-N,N′,N′-trimethyl-ethane    dihydrochloride-   N-{4-[2-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-1-yl-phenyl}-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine-   4-{1-[4-(1-Methyl-piperidin-4-yloxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine-   4-{1-[4-(3-Dimethylamino-propyl)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine-   4-[1-(4-Dimethylamino-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   {4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}acetonitrile-   4-{1-[4-((S)-1-Methyl-pyrrolidin-2-ylmethoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine-   N-{4-[2-(4-amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-C-dimethylamino-acetamide-   N-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-N′,N′-dimethyl-ethane-1,2-diamine-   4-{1-[3-(2-Dimethylamino-ethyloxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}furazan-3-ylamine-   4-{1-[3-(3-Dimethylamino-propoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine-   1-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-3-methyl-urea-   4-{1-[3-(1-Methyl-piperin-4-yloxy)-phenyl]-1H-imidazo[4,5-c]pyridine-2-yl}furazan-3-ylamine-   4-{1-[4-(2-Piperidin-1-yl-ethoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine-   4-{1-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine-   4-{1-[4-(2-Dimethylamino-1-methyl-ethoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine-   4-(1-{4-[2-(Benzyl-methyl-amino)-ethoxy]-phenyl}-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine-   2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-acetamide-   2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-N-methyl-acetamide-   2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-N,N-dimethylacetamide-   2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}ethanol-   3-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-propan-1-ol-   3-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-propionitrile-   N-(2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxyethyl)-isonicotinamide-   N-(2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-ethyl)-acetamide-   Isoxazole-5-carboxylic acid    (2-{4-[2-(4-amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-ethyl)-amide-   N-(2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-ethyl)-methanesulfonamide-   2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-propionamide-   2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-2-methyl-propionamide-   (2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-ethyl)-carbamic    acid tert-butyl ester-   4-{1-[4-(2-Methylamino-ethoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine-   4-{1-[4-(2-Amino-ethoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine-   4-[1-(4-Methylsulfanylmethoxy-phenyl)-1H-imidazo[4,5]pyridin-2-yl]-furazan-3-ylamine-   4-[1-(4-Benzenesulfinylmethoxy-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   4-[1-(4-Benzenesulfonylmethoxy-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   4-[1-(4-Methanesulfinylmethoxy-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   4-[1-(4-Phenylsulfanylmethoxy-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   N-(2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]-pyridin-1-yl}-phenoxy}-ethyl)-benzenesulfonamide-   (2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-cpyridin-1-yl]-phenoxy}-ethyl)-urea-   N-(2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-ethyl)-benzamide-   3,5-Dimethyl-isoxazole-4-sulfonic acid    (2-{4-[2-(4-amino-furazan-3-yl)-imidazo[4,5-c-pyridin-1-yl]-phenoxy}-ethyl)-amide-   N-[5-(2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-ethylsulfamoyl)-4-methyl-thiazol-2-yl]-acetamide-   4-[1-(4-Methanesulfonylmethoxy-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   N-(2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]-pyridin-1-yl]-phenoxy}-ethyl)-benzenesulfonamide-   4-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]phenoxy}-piperidine-1-carboxylic    acid benzyl ester-   4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenol-   2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridine-7-carboxylic    acid (piperidin-2-ylmethyl)amide-   2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridine-7-carboxylic    acid [1-((S)-1-pyrolidin-2-yl-methanoyl)-piperidin-4-yl]-amide-   2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridine-7-carboxylic    acid [1-(2-amino-ethanoyl)-piperidin-4-yl]-amide-   N-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-cyclohexane-1,4-diamine-   2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridine-7-carboxaldehyde-   2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridine-7-carboxylic    acid [1-(3-amino-propanoyl)-piperidin-4-yl]-amide-   [2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-piperidin-4-yl-amine-   4-(4-Chloro-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine-   4-{1-Ethyl-7-[(3-piperazin-1-yl-propylamino)-methyl]-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine-   4-(1-Ethyl-7-{[(3-(4-methyl-piperazin-1-yl)-propylamino]-methyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine-   [2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-[1-(2-methoxy-ethyl)-piperidin-4-yl]-amine-   4-[1-Ethyl-7-((R)-2-piperazin-1-ylmethyl-pyrrolidin-1-ylmethyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine-   2-   {3-[2-(4-Amino-furazan-3-yl)-1H-imidazo[4,5-c]pyridin-1-yl]-propyl}-carbamic    acid tert-butyl ester-   4-(1-Cyclohexylmethyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine-   [2-(4-Amino-furazan-3-yl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-piperidin-4-yl-amine-   4-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-piperazine-1-carboxylic    acid tert-butyl ester-   4-(3-Ethyl-3H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine-   3-(1-Ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-pyrazin-2-ylamine    and physiologically acceptable salts thereof.

The ability of the compounds of formula (I) to antagonise the effect ofthe kinase Msk-1 may be determined using published procedures such asthose described in WO9967283 and WO0127315. Alternatively the followingin vitro assay may be used.

Thus the Msk-1 antagonist activity was determined using humanrecombinant Msk-1 expressed in Sf9 cells (WO9967283). The enzymeunderwent prior activation by incubation with MAPK (p42), which wasremoved prior to storage and subsequent assay. The assay of Msk-1activity involved incubation with peptide substrate and ATP³³, thesubsequent incorporation of P³³ into the peptide was quantified byScintillation Proximity Assay (SPA—Amersham Pharmacia).

For IC50 determination, test compounds were typically dissolved at 10 mMin 100% DMSO, with subsequent serial dilution into 10% DMSO. Compoundswere typically assayed over an eleven point dilution range with aconcentration in the assay of 10 uM to 3 nM, in duplicate. IC50 valueswere calculated by bespoke curve fitting software.

Assays were performed in clear bottomed, white walled, 384 well plates,in a total assay volume of 12.5 ul. The assays contained: 2 nM activatedMSK1; 2 uM biotinylated peptide (biotin-GRPRTSSFAEG-OH); 20 uM ATP; 25Bq per pmole ATP³³; 50 mM Hepes; 10 mM MgCl₂; 0.1 mM EDTA; 0.0025%Tween-20; 5 mM β-Mercaptoethanol; pH 7.5. The reactions were incubatedat 20° C. for 60 minutes, then terminated by the addition of 10 ul of200 mM EDTA.

Streptavidin PVT SPA beads were added to a concentration of 0.2 mg perwell. The plates were shaken for 10 minutes before centrifugation at2500 rpm for 10 minutes. P³³ incorporation was quantified byscintillation counting in a Wallac Trilux.

The compounds of the invention are therefore useful in the treatment orprevention of diseases and/or conditions mediated through the kinaseMsk-1. Thus the compounds are useful for the treatment or prophylaxis ofdisorders associated with neuronal degeneration resulting from ischemicevents or inflammatory conditions. Examples of such disorders includeacute stroke e.g. cerebral stroke, thromboembolic stroke, hemorrhagicstroke and cerebral ischemia, multi infarct dementia, pain, arthritise.g. rheumatoid arthritis, osteoarthritis, psoriasis, and enteropathicarthritis, multiple sclerosis, Alzheimers disease, Parkinson's disease,amyotrophic lateral sclerosis, spinal cord injury and asthma. Thecompounds may also be useful for the treatment of irritable bowelsyndrome, inflammatory bowel disease and certain cancers.

The invention therefore provides for the use of a compound of formula(I) and/or physiologically acceptable salts thereof for use in therapyand in particular for use as a medicine for inhibiting the effects ofthe kinase Msk-1.

The invention also provides for the use of a compound of formula (I)and/or a physiologically acceptable derivative or salt thereof for themanufacture of a medicament for inhibiting the effects of the kinaseMsk-1.

According to a further aspect, the invention also provides for a methodfor inhibiting the effects of the kinase Msk-1 in a mammal e.g. a human,comprising administering to a patient in need thereof an effectiveamount of a compound of formula (I) and/or a physiologically acceptablederivative or salt thereof.

The ability of the compounds of formula (I) to antagonise the effect ofthe kinase ROCK1 may be determined by using the following assays:

1. ROCK Kinase Assay:

ROCK inhibitor activity was determined using human recombinant ROCK1kinase domain (amino acid 1-578) expressed in Sf9 cells (WO9967283). Theenzyme was purified using his-tag NTA column and Source 15 HPLCchromatography. The assay of Rock-1 activity involved incubation withpeptide substrate and ATP³³, the subsequent incorporation of P³³ intothe peptide was quantified by Scintillation Proximity Assay(SPA—Amersham Pharmacia).

For IC50 determination, test compounds were typically dissolved at 10 mMin 100% DMSO, with subsequent serial dilution into 10% DMSO. Compoundswere typically assayed over an eleven point dilution range with aconcentration in the assay of 10 uM to 3 nM, in duplicate. IC50 valueswere calculated by bespoke curve fitting software.

Assays were performed in clear bottomed, white walled, 96 well plates,in a total assay volume of 40 ul. The assays contained: 1 nM hROCK11; 1uM biotinylated peptide (biotin-Ahx-AKRRRLSSLRA-CONH2); 1 uM ATP; 25 Bqper pmole ATP³³; 12.5 mM Hepes pH7.4; 7.5 mM MgCl₂; 0.015% BSA. Thereactions were incubated at 20° C. for 120 minutes, then terminated bythe addition of 10 ul of 200 mM EDTA.

Streptavidin PVT SPA beads were added to a concentration of 0.4 mg perwell. The plates were shaken for 10 minutes before centrifugation at2500 rpm for 10 minutes. P³³ incorporation was quantified byscintillation counting in a Wallac Trilux.

2. Aorta Artery Contraction Assay:

Male Sprague-Dawley rats (350-400 g) are anesthetized with 5% Isofluranein O₂ and euthanized by exsanguination. Proximal descending thoracicaortae are removed and placed in oxygenated (95% O₂, 5% CO₂) ambienttemperature Krebs solution (pH 7.4) with the following composition (mM):NaCl 112.0, KCl 4.7, CaCl₂ 2.5, KH₂PO₂ 1.2, MgSO₄ 1.2, NaHCO₃25.0,dextrose 11.0, indomethacin 0.01, and L-NAME 0.1. The isolated aortaeare cut into four 3 mm rings and each segment is suspended by two 0.1 mmdiameter tungsten wire hooks and placed in a 10 mL organ bath containingoxygenated (95% O₂, 5% CO₂) 37° C. Krebs solution (pH 7.4). The tissuesare equilibrated under 1.0 grams resting tension for approximately 30minutes. Responses are measured isometrically using a Grass FT 03force-transducer and recorded on a Grass polygraph (model 7D) as changein tension.

After the equilibration period, each tissue is contracted with 60 mM KClfor about 15 minutes, washed with 37° C. Krebs solution, and allowed torelax to the resting tension. The 60 mM KCl contraction is repeated. Thetissue is then contracted to equilibration with 1 M norepinephrine andwashed with 37° C. Krebs solution and allowed to relax to the restingtension.

A cumulative concentration-response curve to phenylephrine is obtainedby dosing at 0.5 log unit intervals (1 nM to 1 M) and the EC₈₀ isdetermined. Following several washes, each vessel is contracted toequilibrium with an EC₈₀ concentration of phenylephrine and tone isreversed by adding cumulative amounts of a ROCK inhibitor at 0.5 logunit intervals (0.1 nM to 3 M). When constructing cumulativeconcentration-response, a higher concentration of vasoactive agent isadded to the tissue bath after the previous response has reached aplateau.

3. In Vivo Effect of ROCK Inhibitors (Intravenous, IV):

Rats are anesthetised with isoflurane 3% for the implantation of femoralvenous and arterial catheters. During the experiment, anaesthesia wasmaintained at 2%. Each rat received an intravenous bolus dose of vehiclefollowed by a bolus doses of ROCK inhibitors at 10, 30, 100 and 300ug/kg with approx 20 minutes between doses. Blood samples are taken at20 minutes after doses 10, 30 and 300 ug/kg for the subsequentdetermination of plasma levels of ROCK inhibitors.

Arterial blood pressure and heart rate derived from the blood pressureare recorded on strip chart and also on a computerised data acquisitionsystem (Po-Ne-Mah, V 3.30, Gould Instruments). Hemodynamic data ispresented as the maximum change from pre-dose control expressed asmeans+/−SEM.

The compounds of the invention are therefore useful in the treatment orprevention of diseases and/or conditions mediated through Rho kinases-1and/or -2.

Thus the compounds are useful for the treatment or prophylaxis ofcardiovascular diseases such as hypertension, chronic and congestiveheart failure, cardiac hypertrophy, restenosis, chronic renal failureand atherosclerosis. The compounds are useful for the treatment orprophylaxis of disorders associated with neuroinflammatory diseases suchas stroke, spinal cord injury, multiple sclerosis, Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis and/or inflammatorydisorders such as inflammatory pain, as rheumatoid arthritis, irritablebowel syndrome, inflammatory bowel disease.

The compounds are useful for the treatment or prophylaxis of asthma,female sexual dysfunction, male erectile dysfunctions and over-activebladder syndrome, cancer and tumor metastasis, viral and bacterialinfections, insulin resistance and diabetes. The invention thereforeprovides for the use of a compound of formula (I) and/or physiologicallyacceptable salts thereof for use in therapy and in particular for use asa medicine for inhibiting the effects of Rho kinases-1 and/or -2.

The invention also provides for the use of a compound of formula (I)and/or a physiologically acceptable derivative or salt thereof for themanufacture of a medicament for inhibiting the effects of Rhokinase-1/2.

The invention also provides for a method for inhibiting the effects ofthe Rho kinase-1/2 in a mammal e.g. a human, comprising administering toa patient in need thereof an effective amount of a compound of formula(I) and/or a physiologically acceptable derivative or salt thereof.According to a further aspect, the invention also provides for a methodfor inhibiting the effects of the kinases Msk-1 and/or Rho kinase-1/2 ina mammal e.g. a human, comprising administering to a patient in needthereof an effective amount of a compound of formula (I) and/or aphysiologically acceptable derivative or salt thereof.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylaxis as well as the treatment ofestablished diseases or symptoms.

It will further be appreciated that the amount of a compound of theinvention required for use in treatment will vary with the nature of thecondition being treated, the route of administration and the age and thecondition of the patient and will be ultimately at the discretion of theattendant physician. In general however doses employed for adult humantreatment will typically be in the range of 5 to 800 mg per day,dependent upon the route of administration.

Preferred routes of administration include by intravenous injection ororally.

Thus for parenteral administration a daily dose regimen will typicallybe in the range 0.1 to 80 mg/kg of the total body weight, preferablyfrom about 0.2 to 30 mg/kg or more preferably 0.5 to 15 mg/kg. For oraladministration a daily dose regimen will typically be within the rangerange 0.1 to 80 mg/kg of the total body weight, preferably from about0.2 to 30 mg/kg or more preferably 0.5 to 15 mg/kg.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example as two,three, four or more sub-doses per day.

While it is possible that, for use in therapy, a compound of theinvention may be administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation.

The invention thus further provides a pharmaceutical formulationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof together with one or more pharmaceutically acceptablecarriers thereof and, optionally, other therapeutic and/or prophylacticingredients. The carrier(s) must be ‘acceptable’ in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The compositions of the invention include those in a form especiallyformulated for oral, buccal, parenteral, inhalation or insufflation,implant or rectal administration. Appropriate dosage forms foradminisration by each of these routes may be prepared by conventionaltechniques.

Tablets and capsules for oral administration may contain conventionalexcipients such as binding agents, for example, syrup, acacia, gelatin,sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone;fillers, for example, lactose, sugar, microcystalline cellulose,maize-starch, calcium phosphate or sorbitol; lubricants, for example,magnesium stearate, stearic acid, talc, polyethylene glycol or silica;disintegrants, for example, potato starch or sodium starch glycollate,or wetting agents such as sodium lauryl sulphate. The tablets may becoated according to methods well known in the art. Oral liquidpreparations may be in the form of, for example, aqueous or oilysuspensions, solutions emulsions, syrups or elixirs, or may be presentedas a dry product for constitution with water or other suitable vehiclebefore use. Such liquid preparations may contain conventional additivessuch as suspending agents, for example, sorbitol syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats; emulsifying agents, for example, lecithin, sorbitan mono-oleate oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters, propyleneglycol or ethyl alcohol; solubilizers such as surfactants for examplepolysorbates or other agents such as cyclodextrins; and preservatives,for example, methyl or propyl p-hydroxybenzoates or ascorbic acid. Thecompositions may also be formulated as suppositories, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The composition according to the invention may be formulated forparenteral administration by injection or continuous infusion.Formulations for injection may be presented in unit dose form inampoules, or in multi-dose containers with an added preservative. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents such assuspending, stabilising and/or dispersing agents. Alternatively theactive ingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile, pyrogen-free water, before use.

Conveniently the compounds of the invention are formulated forintravenous or oral administration.

The compositions according to the invention may contain between 0.1-99%of the active ingredient, conveniently from 30-95% for tablets andcapsules and 3-50% for liquid preparations.

Compounds of formula (I) wherein R₁ is a group (a), (c) and (d) may beprepared by reacting the diamine (II)

wherein R₂, X₁, X₂, X₃ and X₄ have the meanings defined in (I) with theappropriate compound of formula (III), (IV) or (V)

wherein Y is hydrogen, halogen e.g. Cl, Br or I, hydroxy or C₁₋₄alkoxy,Ra is hydrogen or a nitrogen protecting group such as an alkoxycarbonylor benzyloxycarbonyl group and each of X₅, X₆, X₉, X₁₀, X₁₁, X₁₂ and X₁₃have the meanings as defined in formula (I) or is a group availablethereto, followed when required by removal of the nitrogen protectinggroup Ra using conventional methods.

When Y is a group selected from halogen, alkoxy or hydroxy the reactionis carried out with heating and optionally in the presence of a solventand/or a dehydrating agent such as polyphosphoric acid.

When Y is hydrogen the reaction is conveniently carried out in thepresence of an oxidant such as sodium bisulphite.

Compounds of formula (I) wherein R, is the group (b) may be prepared byreduction of the corresponding nitro derivative (VI)

wherein R₂, R₃, R₃, X₁, X₂, X₃, X₄, X₇ and X₈ have the meanings definedin formula (I).

The reduction may be effected using conventional procedures forconverting a nitro group into an amino group, thus for example, thereduction may be effected using hydrogen and a suitable metal catalyste.g. palladium.

Compounds of formula (I) wherein R₁ is the group (c) and X₉ is oxygenand X₁₀ is nitrogen may be prepared by reacting the nitrile (VII)

wherein R₂, X₁, X₂, X₃ and X₄ have the meanings defined in formula (I)with hydrochloric acid and sodium nitrite in a solvent such as analkanol and treatment of the product thus formed with a base e.g.aqueous sodium hydroxide and hydroxylamine and subsequent heating.

Compounds of formula (I) wherein R₁ represent the group (c) wherein X₉is NH and X₁₀ is CH may be prepared by reacting compound (VII)

wherein R₂, X₁, X₂, X₃ and X₄ have the meanings defined in formula (I)with hydrazine. This reaction is preferably carried out in a solvente.g. an alkanol such as methanol and with heating.

In another aspect of the invention compounds of formula (I) may beconverted into other compounds of formula (I). Thus N-oxides ofcompounds of formula (I) may be prepared by treating a compound offormula (I) with a peroxy acid such as hydrogen peroxide in acetic acid.

For example reactions of a compound of formula (I) wherein X₂ or X₃ is Nmay be converted into the corresponding N-oxide i.e. X₂ or X₃ is N═O byreaction with hydrogen peroxide in acetic acid.

A compound of formula (I) wherein R₄ or R₆ is halogen e.g. chlorine orbromine may be prepared from the of formula (I) wherein X₂ is N═O andX₁, is CH or X₃ is N═O and X₄ is CH by reaction with the appropriatephosphorus oxyhalide e.g. phosphorus oxychloride or oxybromide.

Compounds of formula (I) wherein R₆ is alkoxy e.g. methoxy may beprepared by treating the corresponding compound wherein R₆ is halogene.g. chlorine or bromine with the appropriate alkanol e.g. methanol inthe presence of a base such as sodium hydroxide.

Compounds of formula (I) wherein R₃ or R₆ is an optionally substitutedaryl e.g. optionally substituted phenyl group or an optionallysubstituted heteroaryl group may be prepared by treating thecorresponding compound wherein R₃ and or R₆ is halogen e.g. chlorine orbromine by reaction with the corresponding optionally substituted arylor heteroarylboronic acid in the presence of a suitable palladiumcatalyst e.g. bis(triphenylphosphine)palladium(II) dichloride ortetrakis(triphenylphosphine)palladium(0) or1,1-bis(triphenylphosphono)ferrocene dichloropalladium(II) chloroformcomplex and a base e.g. sodium carbonate. The reaction is preferablycarried out in a solvent e.g. hydrocarbon such as toluene or ether suchas 1,2-dimethoxyether or an amide such as DMF and with heating.

Compounds of formula (I) wherein R₃ is a group R₁₉S or R₁₉NH and whereinR₁₉ is an optionally substituted aryl e.g. optionally substituted phenylgroup or an optionally substituted heteroaryl group may be prepared bytreating the corresponding compound wherein R₃ is halogen e.g. brominewith the corresponding thiol R₁₉SH or amine R₁₉NH₂ in the presence of asuitable palladium catalyst e.g. Tris(dibenzylidene-acetone)dipalladiumand racemic-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl The reaction ispreferably carried out in a solvent e.g. an ether such as dioxane withheating.

Compounds of formula (I) wherein R₃ is a group the group SO₂NR₁₄R₁₅ maybe prepared by treating the corresponding compound wherein R₃ is halogene.g. bromine with the sodium hydride and then n-butyllithium and thetreating the resultant product sequentially with sulphur dioxide,sulphuryl chloride and then the amine HNR₁₄R₁₅. The reaction isconveniently carried out in a solvent such as tetrahydrofuran.

Compounds of formula (I) wherein R₆ is an alkyl group e.g methyl may beprepared by treating the corresponding compound wherein R₆ is halogene.g. bromine by reaction with the corresponding trialkylaluminium in thepresence of bis(triphenylphosphine)palladium(II) dichloride. Thereaction is preferably carried out in a solvent e.g. 1,4 dioxan and withheating.

Compounds of formula (I) in which R₂ and/or R₃ contain a phenyl groupsubstituted by a methoxy group, as a substituent or part of asubstituent may be converted into the corresponding compound of formula(I) wherein the phenyl group is substituted by hydroxy, by reaction withboron tribromide in a suitable solvent such as dichloromethane.

Compounds of formula (I) wherein R₂ is a phenyl group substituted by anoptionally substituted alkoxy group e.g. a dialkylaminoalkoxy group maybe prepared by reacting the corresponding compound of formula (I)wherein R₂ is a phenyl group substituted by hydroxy with a suitable basee.g. sodium hydride in an aprotic solvent such as dimethylformamide andthen the appropriate optionally substituted alkylhalide e.g.dialklaminoalkylhalide.

Compounds of formula (I) wherein R₃ is bromine may be converted into thecorresponding wherein R₃ is formyl by reaction with n-butyllithium anddimethylformamide in a solvent such as tetrahydrofuran followed byquenching with water.

Compounds of formula (I) wherein R₃ is carboxyl may be prepared from thecorresponding compound of formula (I) wherein R₃ is bromine by reactionwith lithium disopropylamide and then butyl lithium in hexanes followedby treatment with carbon dioxide gas. The reaction is preferably carriedout at a low temperature e.g. −78° C.

Compounds of formula (I) wherein R₃ is a methyl group substituted by agroup selected from R₁₉NH, R₁₉R₂₀N, or an N linked, 4-7 memberedheterocyclic group (containing one or two hetero atoms selected from N,O or S(O)n), may be prepared by reaction of the corresponding compoundwherein R₃ is formyl with the appropriate amine R₁₉NH₂, R₁₉R₂₀NH or 4-7membered heterocycle under reductive alkylation conditions. For exampleusing a cyanoborohydride in a suitable solvent e.g. methanol. In thisreaction if the groups R₁₉, R₂₀ or the 4-7 membered heterocycle containsan additional primary or secondary amino group then it is desirable toprotect these using a conventional nitrogen protecting group such as at-butyloxycarbonyl which may then be deprotected if so required.

Compounds of formula (I) wherein R₂ or R₃ is phenyl substituted by aminomethyl and wherein the amino group refers to a group R₁₉NH, R₁₉R₂₀N oran N linked 4-7 membered heterocyclic group containing one or twoheteatoms selected from N, O or S(O)n may be prepared by reacting thecorresponding compound wherein R₂ or R₃ is phenyl substituted by CHOunder conventional reductive alkylation conditions such as thosedescribed above for preparing compounds wherein R₃ is methyl substitutedby R₁₉NH or R₁₉R₂₀N. The compounds of formula (I) wherein R₂ is phenylsubstituted by CHO may br prepared in situ from the correspondingcompound wherein R₂ is phenyl substituted by halogen e.g. bromine byreaction with n-butyllithium and dimethylformamide in a solvent such astetrahydrofuran followed by quenching with water.

Compounds of formula (I) wherein R₃ is the group CONR₁₄R₁₅ and R₁₄ andR₁₅ have the meanings defined in formula (I) may be prepared from thecorresponding compounds of formula (I) wherein R₃ is carboxyl byreaction with the amine HNR₁₄R₁₅ wherein R₁₄ and R₁₅ have the meaningsdefined in formula (I) or are protected derivatives thereof underconventional procedures for preparing amides from acid followed byremoval of the said protecting groups.

Conventionally the reaction is carried out by treating the acid withcarbonyldimidiimidazole in a suitable solvent such as DMF followed byreaction with the amine HNR₁₄R₁₅.

Compounds of formula (I) wherein R₃ is hydroxyl may be prepared from thecorresponding compound wherein R₃ is halogen e.g. bromine by reactionwith n-butyl lithium in a solvent such as tetrahydrofuran or hexanes andtetrahydrofuran followed by addition of a trialkyl borate such astrimethylborate. The reaction is preferably carried out at lowtemperatures e.g. 78° C. and then allowed to reach room temperaturebefore being quenched by aqueous sodium hydroxide followed by aqueoushydrogen peroxide.

Compounds of formula (I) wherein R₃ is the group R₁₉O and wherein R₁₉has the meaning defined in formula (I) hydroxyl may be prepared from thecorresponding compound wherein R₃ is hydroxyl by reaction with a groupR₁₉La wherein R₁₉ has the meaning defined in formula (I) is a protectedderivative thereof and La is a leaving group. Thus La can be a halogengroup e.g. bromines or iodine, or a hydroxyl which can be converted intoa leaving group insitu e.g. by reaction with tributylphosphine andazodicarbonyl) dipiperidine.

Compounds of formula (I) wherein R₃ is an optionally substituted ethenylgrouping may be prepared by a compound of formula (I) wherein R₃ isbromine by reaction with the appropriate ethene derivative in thepresence of palladium acetate, or tolyltriphenylphosphine and a teritaryorganic base such as triethylamine.

Compounds wherein R₃ is an optionally substituted ethyl group may beprepared by treating the corresponding compound of formula (I) whereinR₃ is halogen e.g. bromine by reaction with the corresponding optionallysubstituted ethenyl compound in the presence of9-borobicyclo[3,3.1]-nonane and 1,1 bis(diphenylphosphono ferrocenedichloro palladium complex in a suitable solvent such as tetrahydrofuranand or dichloromethane.

In the above synthesis of compounds of formula (I) wherein they containa primary or secondary amino grouping it may be necessary or desirableto carry out these procedures wherein the primary or secondary amine isin a protected form e.g. as a carbamate e.g. a t-butyl carbamate andthen the carbamate converted into the required amine by conventionalprocedures, for example by the reaction with trifluoroacetic acid.

The nitrile of formula (VII) may be prepared by heating of a compound offormula (II) with ethyl cyanoacetate.

The compound of formula (VIII) may be prepared by reacting the nitrileof formula (VII) with an acetal of N,N dimethylformamide in a solvente.g. a hydrocarbon such as ortho xylene and with heating.

Compounds of formula (VI) may be prepared by reaction of the2-iodo-imidazole derivative (IX)

wherein R₂, X₁, X₂, X₃ and X₄ have the meanings defined in formula (I)with the compound (X)

wherein X₇ and X₈ have the meanings defined in formula (I) in thepresence of a base and a polar aprotic solvent and then reacting theresultant compound (XI)

with an alkyl nitrite in the presence of a suitable base.

Compounds of formula (II) may be prepared by reacting a compound offormula (XII)

wherein X₁, X₂, X₃ and X₄ have the meanings defined above and L is agroup displaceable by the amine R₂NH₂ e.g. methoxy, bromine, chlorine,fluorine or methoxysulphonyl to give the nitro amine (XIII)

followed by reduction of the nitro group by conventional means, forexample using hydrogen and a palladium catalyst, iron and an organicacid e.g. acetic acid or with sodium dithionate.

When compounds of formula (I) contain an asymmetric centre the specificenantiomers arising there from may be obtained by conventionalprocedures. For example using preparative high performance liquidchromatography (HPLC) with a chiral stationary phase.

Physiologically acceptable acid addition salts of the compounds offormula (I) may be prepared by conventional procedures, for example byaddition of a solution of the inorganic or organic acid in a suitablesolvent e.g. an alkanol or an ether to a solution of the free base in asolvent such as an alkanol, e.g. methanol or an ether e.g. diethyl etheror tetrahydrafuran.

The compounds of formula (III), (IV), (V) (IX), (X) and (XII) are eitherknown compounds or may be prepared by analogous methods to thosepreparing the known compounds.

The following examples are illustrative of the present invention and arenot to be construed as a limitation of the scope of the invention.

EXAMPLE 1 4-(1-Ethyl-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

Step 1. Ethyl-(3-nitropyridin-4-yl)amine

4-Methoxy-3-nitropyridine hydrochloride (11.2 g, 58.9 mmol) in ethanol(75 ml) was treated with a 70% solution of ethylamine in water (32 ml)and heated under reflux for 1 hour. Further ethylamine solution (32 ml)was added and the mixture heated under reflux for a further 2 hours.After cooling to room temperature, the solvent was removed in vacuo andthe residue dissolved in ethyl acetate, washed (×3) with water andsaturated aqueous sodium chloride solution, dried over sodium sulphateand concentrated in vacuo to afford the title compound (8.7 g, 88%); MS(ES+) m/e 168 [M+H]⁺.

Step 2. N⁴-Ethylpyridine-3,4-diamine

The product from Step 1 (8.7 g, 52.0 mmol) in ethanol (150 ml) washydrogenated for 18 hours in the presence of 10% palladium on carbon.After filtration of the catalyst through Kieselguhr, the filtrate wasconcentrated in vacuo to afford the title compound (6.7 g, 94%); MS(ES+) m/e 138 [M+H]⁺.

Step 3. (1-Ethyl-1H-imidazo[4,5-c]pyridin-2-yl)acetonitrile

The product from Step 2 (500 mg, 3.6 mmole) and ethyl cyanoacetate (620mg, 5.5 mmol) were heated together at 190° C. for 20 minutes. Aftercooling to room temperature, the residue was purified by columnchromatography eluting with 10% methanol in ethyl acetate to afford thetitle compound (250 mg, 37%); MS (ES+) m/e 187 [M+H]⁺.

Step 4. 4-(1-Ethyl-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

The product from Step 3 (200 mg, 1.1 mmol) in methanol (4 ml) and 2Nhydrochloric acid (4 ml) was treated portionwise with sodium nitrite(150 mg, 2.2 mmol) and stirred at room temperature for 2 hours. The pHof the mixture was adjusted to 12 by addition of 50% sodium hydroxidesolution and a 50% solution of hydroxylamine in water (3 ml) was added.The mixture was heated at 90° C. for 2.5 hours and the reaction allowedto cool to room temperature. The resulting precipitate was filtered anddried in vacuo to afford the title compound (110 mg, 43%); MS (ES+) m/e231 [M+H]⁺.

EXAMPLE 24-(1-Cyclopropyl-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

Step 1. Cyclopropyl-(3-nitropyridin-4-yl)amine

4-Methoxy-3-nitropyridine hydrochloride (2.0 g, 11.3 mmol) andcyclopropylamine (1.6 ml, 22.6 mmol) in ethanol (5 ml) was treated withtriethylamine (1.7 ml, 12.4 mmol) and heated under reflux for 18 hours.After cooling to room temperature, the solvent was removed in vacuo andthe residue dissolved in dichloromethane, washed with water andsaturated aqueous sodium chloride solution, dried over magnesiumsulphate and concentrated in vacuo to afford the title compound (1.7 g,84%); MS (AP+) m/e 180 [M+H]⁺.

Steps 2.4-(1-Cyclopropyl-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

The title compound was prepared from the product of Step 1 using themethods of Example 1 Steps 2-4; MS (AP+) m/e 243 [M+H]⁺.

The following examples were prepared by the general two-step methoddescribed in Example 2.

Example Amine Characterisation 3 4-(1-Methyl-1H-imidazo[4,5- Methylamine(8M in MS(AP+) m/e c]pyridin-2-yl)furazan-3-ylamine ethanol) 217 [M +H]⁺ 4 4-(1-Cyclohexyl-1H- Cyclohexylamine MS (ES+) m/eimidazo[4,5-c]pyridin-2- 285 [M + H]⁺. yl)furazan-3-ylamine 54-(1-Cyclopropylmethyl-1H- Cyclopropylmethylamine MS(AP+) m/eimidazo[4,5-c]pyridin-2- 257 [M + H]⁺ yl)furazan-3-ylamine 64-(1-Cyclohexylmethyl-1H- Cyclohexylmethylamine MS(AP+) m/eimidazo[4,5-c]pyridin-2- 299 [M + H]⁺ yl)furazan-3-ylamine 74-(1-Cyclobutyl-1H- Cyclobutylamine MS(AP+) m/e imidazo[4,5-c]pyridin-2-257 [M + H]⁺ yl)furazan-3-ylamine 8 4-[1-(2-Ethylbutyl)-1H-2-Ethyl-N-butylamine MS(AP+) m/e imidazo[4,5-c]pyridin-2- 288 [M + H]⁺yl)furazan-3-ylamine 9 4-(-Isopropyl-1H-imidazo[4,5- IsopropylamineMS(AP+) m/e c]pyridin-2-yl)furazan-3- 245 [M + H]⁺ ylamine 104-(1-sec-Butyl-1H-imidazo[4,5- sec-Butylamine MS(AP+) m/ec]pyridin-2-yl)furazan-3- 259 [M + H]⁺ ylamine 11 4-(1-Cyclopentyl-1H-Cyclopentylamine MS(AP+) m/e imidazo[4,5-c]pyridin-2-yl)- 271 [M + H]⁺furazan-3-ylamine 12 4-(1-Cycloheptyl-1H- Cycloheptylamine MS(AP+) m/eimidazo[4,5-c]pyridin-2-yl- 299 [M + H]⁺ furazan-3-ylamine 134-[1-(2-Dimethylamino-1- N¹,N¹-Dimethyl-1,2- MS(AP+) m/emethylethyl)-1H-imidazo[4,5- propanediamine 288 [M + H]⁺c]pyridin-2-yl)furazan-3- ylamine 14 4-(1-Piperidin-4-yl)-1H-4-Amino-piperidine-1- MS(AP+) m/e imidazo[4,5-c]pyridin-2-yl- carboxylicacid tert-butyl 286 [M + H]⁺ furazan-3-ylamine ester 154-[1-(4-Diethylamino-1-methyl- 2-amino-5-diethylamino MS (AP+) m/ebutyl)-1H-imidazo[4,5-c]pyridin- pentane 344 [M + H]⁺2-yl]-furazan-3-ylamine 16 {4-[2-(4-Amino-furazan-3-yl)-(4-Amino-butyl)-carbamic MS (ES+) m/e imidazo[4,5-c]pyridin-1-yl]- acidtert-butyl ester 374[M + H]⁺ butyl}-carbamic acid tert-butyl ester 174-[1-(3-Dimethylamino-propyl)- N¹,N¹-Dimethyl- MS (ES+) m/e1-H-imidazo[4,5-c]pyridin-2- propane-1,3-diamine 288 [M + H]⁺.yl]-furazan-3-ylamine (Monatsh. Chem. 112, 825-840 (1981)) 184-{1-[2-(4-Methyl-piperazin-1- 2-(4-Methyl-piperazin-1- MS (ES+) m/eyl)-ethyl]-1-H-imidazo[4,5- yl)-ethylamine 329 [M + H]⁺.c]pyridin-2-yl}-furazan-3- (J. Med. Chem. 42 (15) ylamine 2870-2880(1999))

EXAMPLES 19 AND 20(+)-4-[1-(2-Dimethylamino-1-methylethyl)-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamineand(−)-4-[1-(2-Dimethylamino-1-methylethyl)-1-H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

The racemic product of Example 13 was separated into the titleenantiomeric forms by preparative LC using Chiralcel OD, 10 micronparticle size; 250 mm×4.6 mm i.d.; n-Hexane: Ethanol, 99.7% v/v−100% v/v(80:20 v/v); 1.0 ml/min; UV detection at 215 nm yielding the (+)enantiomer [α]D+6.8°; HPLC tR 8.2 min and the (−) enantiomer [α]D−2.2°;HPLC tR 9.0 min.

EXAMPLE 214-[1-(4-Amino-butyl)-1H-imidazo[4,5-c]pyridin-2-yl]4-furazan-3-ylamine

A solution of the product of Example 16 (155 mg, 0.415 mmol) inanhydrous dichloromethane (4 ml) was treated with trifluoroacetic acid(4 ml), and stirred at room temperature for 0.5 hours. The solvent wasevaporated in vacuo and the residue partitioned between dichloromethaneand saturated sodium bicarbonate solution. The organic phase was washedwith water (×3), and dried over anhydrous sodium sulphate, and thesolvent evaporated in vacuo. The residue was purified by silica gelchromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (1:9:90) to afford the title product(52 mg, 46%). MS (ES+) m/e 274 [M+H]⁺.

The following compounds were prepared by the methods of Example 2followed by the method of example 21:

Example Amine Characterisation 22 4-(1-(1-Pyrrolidin-3-amino-pyrrolidine-1- MS (ES+) m/e 3-yl-1-H- carboxylic acid 272 [M +H]⁺. imidazo[4,5- tert-butyl ester c]pyridin-2-yl)- (Syn. Comm. 2357-furazan-3-ylamine 60 (1992) 23 4-[1-(5-Amino-pentyl)- (5-Amino-pentyl)-MS (ES+) m/e 1-H-imidazo[4,5- carbamic acid tert- 288 [M + H]⁺.c]pyridin-2-yl]- butyl ester (J. Med. furazan-3-ylamine Chem. 32(2)391-396 (1989)) 24 4-[1-(3-Amino-propyl)- (3-Amino-propyl)- MS (ES+) m/e1-H-imidazo[4,5- carbamic acid 259 [M + H]⁺. c]pyridin-2-yl]- tert-butylfurazan-3-ylamine ester(J. Org. Chem. 57(21)5687-5692 (1992))

EXAMPLE 254-(1-Piperidin-3-yl-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

Step 1. 3-(3-Nitro-pyridin-4-ylamino-piperidine-1-carboxylic acidtert-butyl ester

4-Chloro-3-nitropyridine (1.1 g, 6.99 mmol) in ethanol (12 ml) wastreated with 3-Amino-piperidine-1-carboxylic acid tert-butyl ester (2.8g, 13.9 mMol) followed by sodium acetate (0.57 g, 6.99 mMol) and heatedunder reflux for 2 hours. After cooling to room temperature, the solventwas removed in vacuo and the residue dissolved in ethyl acetate, washed(×3) with water dried over magnesium sulphate and concentrated in vacuoto afford the title compound (2.1 g, 94%); MS (ES+) m/e 323 [M+H]⁺.

Step 2.4-(1-Piperidin-3-yl-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

The title compound was prepared from the product of step 1 using themethod of example 1 Steps 2 to 4, then example 21. MS (ES+) m/e 286[M+H]⁺.

The following compound was synthesised using the same 2-step procedureused to make example 25.

Name Amine Data 26 4-[1-(2-Piperazin- from 4-(2-Aminoethyl)- MS (ES+)m/e 1-yl-ethyl)-1-H- piperazine-1-carboxylic 315 [M + H]⁺.imidazo[4,5-c]pyridin-2- acid benzyl ester (J. yl]-furazan-3-ylamineMed. Chem. 30(1) 121-131 (1987)

EXAMPLES 27 AND 28(+)-4-(1-Piperidin-3-yl-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamineand(−)-4-(1-Piperidin-3-yl-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

The racemic product of Example 25 was separated into the titleenantiomeric forms by preparative LC using Chiralpak AD, 10 micronparticle size; 250 mm×20 mm i.d.; n-Hexane: Ethanol, (50:50 v/v;pre-mixed); 17 m/min; UV detection at 215 nm yielding the (+) enantiomer[α]D+0.4°; HPLC tR 6.6 min and the (−) enantiomer [α]D−3.2°; HPLC tR 7.7min.

EXAMPLE 294-(1-Piperidin-4-ylmethyl-1H-imidazo(4,5-c)pyridi-2-yl)-furazan-3-ylamine

Step 1. 4-((3-Nitro-pyridin-4-ylamino)-methyl)-piperidine-1-carboxylicacid tert-butyl ester

4-Methoxy-3-nitropyridine hydrochloride (2.26 g, 11.9 mmol) in ethanol(15 ml) was treated with 4-aminomethyl-piperidine-1-carboxylic acidtert-butyl ester (3.05 g, 14.2 mMol) followed by triethylamine (1.82 ml,13.1 mMol) and heated under reflux for 6 hours. After cooling to roomtemperature, the solvent was removed in vacuo and the residue dissolvedin ethyl acetate, washed (×3) with water, brine, dried over sodiumsulphate and concentrated in vacuo to afford the title compound (2.78 g,77%); ¹H NMR (400 MHz) δ 9.21 (1H (s) Ar—H), δ 8.30 (1H, (d) Ar—H), δ8.2 (1H, (s) N—H) δ 6.70 (1H, (d) Ar—H), δ 4.04 (2H (broad), CH₂) δ 3.25(2H, (t) piperidine) δ 2.73 (2H, (broad) piperidine), δ 1.79 (1H,(broad) piperidine), δ 1.46 (9H, (s) ^(t)Bu).

Steps 2.4-(1-Piperidin-4-ylmethyl-1H-imidazo(4,5-c)pyridi-2-yl)-furazan-3-ylamine

The title compound was prepared from the product of step 1 according tothe method of example 1 steps 2-4, followed by the method of example 21.MS (ES+) m/e 300 [M+H]⁺.

EXAMPLE 304-[1-(4-Methoxy-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

Step 1: (4-Methoxy-phenyl)-(3-nitro-pyridin-4-yl)-amine

To a solution of 4-chloro-3-nitropyridine (Kruger J, Mann F. G, J. Chem.Soc., 1955, 2755) (700 mg, 4.41 mmol) in ethanol (10 ml) was added4-methoxyaniline (1.087 g, 8.82 mmol), followed by sodium acetate (362mg, 4.41 mmol). The mixture was heated under reflux for 16 hours, cooledto room temperature and diluted with water (30 ml). The resultingprecipitate was collected by filtration, washed with water (×3) anddried in vacuo to afford the title compound (800 mg, 74%); MS (ES+) m/e309 [M+H]⁺.

Step 2:4-[1-(4-Methoxy-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The title compound was prepared from the product of Step 1 using themethods of Example 1 Step 2-4; MS (AP+) m/e 309 [M+H]⁺.

The following examples were prepared by the general two-step methoddescribed in Example 30.

Example Aniline Characterisation 31 4-(1-Phenyl-1H-imidazo[4,5- AnilineMS (ES+) m/e c]pyridin-2-yl)-furazan-3-ylamine 279 [M + H]⁺ 324-[1-(4-Amino-phenyl)-1H- 4-amino MS (ES+) m/eimidazo[4,5-c]pyridin-2-yl]- acetanilide 294 [M + H]⁺ furazan-3-ylamine33 4-[1-(3-Methoxy-phenyl)-1H- 3-methoxy MS (ES+) m/eimidazo[4,5-c]pyridin-2-yl]- aniline 309 [M + H]⁺ furazan-3-ylamine 344-[1-(2-Methoxy-phenyl)-1H- 2-methoxy MS (ES+) m/eimidazo[4,5-c]pyridin-2-yl]- aniline 309 [M + H]⁺ furazan-3-ylamine 354-[1-(2-Ethyl-phenyl)-1H- 2-ethyl MS (ES+) m/eimidazo[4,5-c]pyridin-2-yl]- aniline 307 [M + H]⁺ furazan-3-ylamine

EXAMPLE 364-[1-(3-Chloro-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

Step 1: (3-Chloro-phenyl)-(3-nitro-pyridin-4-yl)-amine

The title compound was prepared from 3-chloro aniline using theprocedures detailed in Example 30 Step 1.

Step 2: N4-(3-Chloro-phenyl)-pyridine-3,4-diamine

The product of Step 1 (325 mg, 1.302 mmol), was dissolved in ethanol (20ml), and treated with iron powder (727 mg, 13.017 mmol), 20 drops of37%. hydrochloric add and water (2 ml), and refluxed for 1 hour. Thereaction was then filtered hot, and the filtrate evaporated in vacuo.The residue was dissolved in ethyl acetate then washed with saturatedsodium bicarbonate solution, water, and brine, separated, dried overanhydrous sodium sulfate and evaporated in vacuo to afford the titlecompound (253 mg, 88%). MS (ES+), m/e 220/222 [M+H]⁺.

Step 3:4-[1-(3-Chloro-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The title product was prepared using the general method described inExample 1 Step 3-4; MS (ES+), m/e 313/315 [M+H]⁺.

The following example was prepared by the general 3 step methoddescribed in example 36.

37 4-[1-(3-bromo-phenyl)-1H- 3-bromo aniline MS (ES+) m/eimidazo[4,5-c]pyridin-2-yl]- 357/359 [M + H]⁺ furazan-3-ylamine

EXAMPLE 384-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenol

To a solution of the product of Example 30 (100 mg, 0.32 mmol) inanhydrous dichloromethane (1.0 ml) stirred at 0° C., was added dropwisea 10M solution of boron tribromide (2.91 ml, 2.92 mmol) indichloromethane and the mixture stirred at room temperature for 16hours. The reaction was then quenched with water (20 ml), and the pHadjusted to 14 with 50% sodium hydroxide solution. The aqueous phase waswashed with dichloromethane (×3), neutralised with 5N hydrochloric acid,and the resulting precipitate collected, washed with water (×3), diethylether and dried in vacuo to yield the title compound (59 mg, 62%); MS(ES+) m/e 295 [M+H]⁺.

EXAMPLE 393-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenol

The title compound was prepared from the product of Example 33 using theprocedure detailed in Example 38.

EXAMPLE 404-[1-(3-Pyrrolidin-1-ylmethyl-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

Step 1:3-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-benzaldehyde

The product of Example 37 (1.07 g, 3 mmol) in anhydrous tetrahydrofuranat −78° C. was treated dropwise with a 2.5M solution of n-butyllithium(3.6 ml, 9 mmol) in hexanes, followed by anhydrous dimethylformamide (10ml) and stirred for 10 minutes. The reaction was then warmed to roomtemperature, quenched with water and extracted with dichloromethane(×3). The combined organic phase was washed with water, brine, driedover anhydrous sodium sulfate and evaporated in vacuo. The residue waspurified using silica gel chromatography, eluting with a mixture ofethyl acetate/pentane (3:1) to afford the title compound (75 mg, 8%); MS(ES+), m/e 307 [M+H]⁺.

Step 2:4-[1-(3-Pyrrolidin-1-ylmethyl-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The product of Step 1 was stirred in 1,2-dichloroethane, and treatedwith pyrrolidine (27 uL, 0.326 mmol) and stirred for 15 minutes at roomtemperature. The reaction was then treated with sodiumtriacetoxyborohydride (34 mg, 0.164 mmol) and stirred at roomtemperature for 16 hours. The reaction was diluted with methanol andapplied to a Mega Bond Elute SCX ion exchange column, elutingsequentially with water, methanol and finally 0.880 ammonia:methanol(1:9). The residue was purified using silica gel chromatography elutingwith a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) toafford the compound (20 mg, 34%); MS (ES+), m/e 362 [M+H]⁺.

EXAMPLE 414-{1-[4-(2-Dimethylamino-ethoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylaminehydrochloride

To a solution of the product of Example 38 (30 mg, 0.102 mmol), inN,N-dimethylformamide (2 ml), was added sodium hydride (60% dispersionin mineral oil, 4 mg, 0.10 mmol). After 5 minutes at room temperature2-(dimethylamino)ethyl chloride hydrochloride (15 mg, 0.102 mmol) andsodium hydride (60% dispersion in mineral oil, 4 mg, 0.102 mmol) wereadded and the reaction heated at 60° C. for 5 hours. The solvent wasevaporated in vacuo and the residue was partitioned between ethylacetate and 2M sodium hydroxide solution. The organic phase wasseparated then washed with water (×3), dried over anhydrous sodiumsulphate and evaporated in vacuo. Purification of the residue by silicagel chromatography eluting with 10% methanol in dichloromethane gave thefree base of the title compound. The product was dissolved in methanol(1 ml) and treated with a 1M solution hydrochloric acid (36 uL, 0.036mmol) in diethyl ether and evaporated in vacuo to yield the titlecompound (14 mg, 32%); MS (ES+) m/e 366 (M+H]⁺.

EXAMPLE 422-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-acetamidetrifluoroacetate

The product of Example 38 (77.0 mg, 0.0260 mmol) was dissolved inN,N-dimethylformamide (1.5 ml) and sodium hydride (60% dispersion inoil, 11.5 mg, 0.286 mmol) was added (gas evolution!). After 5 minutes atroom temperature, chloroacetamide (36.5 mg, 0.390 mmol) was added andthe solution was heated to 60° C. for 3 hours. The reaction mixture waspartitioned between ethyl acetate and satd. aqueous NaHCO₃. The aqueousphase was washed with EtOAc (×2), dried over anhydrous sodium sulfateand evaporated in vacuo. Purification of the residue by preparative HPLC(0-80% CH₃CN/H₂O (0.1% TFA), retention time=5.35 minutes) afforded thetitle compound as a white solid (58 mg, 48%). MS (ES+) m/e 352 [M+H]⁺.

The following examples were prepared by the general method described inExample 42.

Example Alkyl Halide Characterisation 43 2-{4-[2-(4-Amino-furazan-3-N,N-dimethyl MS(ES+) m/e yl)-imidazo[4,5-c]pyridin-1-yl]-chloroacetamide 366 [M + H]⁺ phenoxy}-N,N- dimethylacetamide 442-{4-[2-(4-Amino-furazan-3- 2-bromoethanol MS(ES+) m/eyl)-imidazo[4,5-c]pyridin-1-yl]- 339 [M + H]⁺ phenoxy}-ethanol 453-{4-[2-(4-Amino-furazan-3- 3-chloropropionitrile MS(ES+) m/eyl)-imidazo[4,5-c]pyridin-1-yl]- 429 [M + H]⁺ phenoxy}-propionitrile 463-{4-[2-(4-Amino-furazan-3- 3-bromopropanol MS(ES+) m/eyl)-imidazo[4,5-c]pyridin-1-yl]- 353 [M + H]⁺ phenoxy}-propan-1-ol 472-{4-[2-(4-Amino-furazan-3- N-Methyl MS(ES+) m/eyl)-imidazo[4,5-c]pyridin-1-yl]- chloroacetamide 366 [M + H]*phenoxy}-N-methyl- acetamide 48 4-[1-(4-Methylsulfanyl- Chloromethylmethyl MS(ES+) m/e methoxyphenyl)-1H- sulfide 355 [M + H]⁺imidazo[4,5-c]pyridin-2-yl]- furazan-3-ylamine 494-[1-(4-Phenylsulfanyl- Chloromethyl phenyl MS(ES+) m/emethoxy-phenyl)-1H- sulfide 433 [M + H]⁺ imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

EXAMPLE 50(2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-ethyl)-carbamicacid tert-butyl ester trifluoroacetate

To a suspension of the product of Example 38 (0.400 g, 1.36 mmol) in1,4-dioxane was added triphenylphosphine (534 mg, 2.04 mmol) and N-BOCethanolamine (0.316 mL, 2.04 mmol). Diisopropylazodicarboxylate (0.401mL, 2.04 mmol) was added. After 14.5 hours, the reaction mixture wasevaporated in vacuo. The resulting residue was purified by preparativeHPLC (0-80% CH₃CN/H₂O (0.1% TFA), retention time=7.75 minutes) affordingthe title compound as the trifluoroacetate salt (383 mg, 51%). MS (ES+)m/e 438 [M+H]⁺.

The following example was prepared according to the general proceduredescribed in Example 50:

Example Alcohol Characterisation 51 4-{1-[4-(2-Methylamino- N-methylMS(ES+) m/e 352 ethoxy)-phenyl]-1H- ethanolamine [M + H]⁺imidazo[4,5-c]pyridin- 2-yl}-furazan-3-ylamine

EXAMPLES 52 AND 534-[1-(4-Benzenesulfinylmethoxy-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamineand4-[1-(4-Benzenesulfonylmethoxy-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The product of Example 49 (28.0 mg, 0.053 mmol) was dissolved inmethanol (0.600 mL) and H₂O (0.300 mL). Sodium periodate (14 mg, 0.065mmol) was added and the reaction was allowed to stir for four days. Thesolution was partitioned between ethyl acetate and aq. NaCl. The organicphase was dried over sodium sulfate, filtered and concentrated. Theresulting residue was purified by preparative HPLC (0-80% CH₃CN/H₂O(0.1% TFA) sulfoxide retention time=6.79 minutes; sulfone=7.45 minutes)to yield the title compounds as their trifluoroacetate salts: Example 52(sulfoxide) (10.0 mg, 35%), MS (ES+) m/e 433 [M+H]⁺; Example 53(sulfone) (3.2 mg, 11%), MS (ES+) m/e 449 [M+H]⁺.

EXAMPLE 544-[1-(4-Methanesulfinylmethoxy-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The title compound was prepared from the product of example 48 accordingto the procedure described for example 52. MS (ES+) m/e 371 [M+H]⁺.

EXAMPLE 55 4-{1[4-(2-Amino-ethoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylaminehydrochloride

The product of Example 50 was treated with 4.0 M HCl/dioxane. After twohours, the reaction was judged complete by LC-MS. The reaction mixturewas concentrated in vacuo to provide the title compound as a whitepowder (245 mg, 86%). MS (ES+) m/e 339 [M+H]⁺.

EXAMPLE 56 Isoxazole-5-carboxylic acid(2-{4-[2-(4-amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy)-ethyl)-amide

The product of example 55 was suspended in dichloromethane (0.5 mL) andtriethylamine (0.025 mL, 0.173 mmol) was added. Isoxaole 5-carbonylchloride (0.010 mL, 0.073 mmol) was added. After 2.5 hours, the reactionmixture was partitioned between ethyl acetate and 2N NaOH. The aqueousphase was washed with ethyl acetate (×1). The combined organic phaseswere washed with satd. aq. NaCl, dried over sodium sulfate, filtered andconcentrated. The resulting residue was purified by preparative HPLC(0-80% CH₃CN/H₂O (0.1% TFA), retention time=6.42 minutes) to yield thetitle compound as the trifluoroacetate salt (7.0 mg, 26%). MS (ES+) m/e433 [M+H]⁺.

The following example was prepared according to the general proceduredescribed in Example 56:

Example Acid Chloride Characterisation 57 N-(2-{4-[2-(4-Amino-furazan-Acetyl chloride MS(ES+) m/e 380 3-yl)-imidazo[4,5-c]pyridin-1- [M + H]⁺yl]-phenoxy}-ethyl)-acetamide

The following example was prepared according to the general proceduredescribed in Example 56, using an additional equivalent oftriethylamine:

58 N-(2-{4-[2-(4-Amino-furazan- isonicotinoyl MS(ES+) m/e3-yl)-imidazo[4,5-c]pyridin-1- chloride 433 [M + H]⁺yl]-phenoxy}-ethyl)- hydrochloride isonicotinamide

EXAMPLE 59(2—[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]-pyridin-1-yl]-phenoxy}-ethyl)-urea

The product of example 55 (25 mg, 0.061 mmol) was dissolved in THF(0.350 mL) and H₂O (0.150 mL). A solution of KOCN (25 mg, 0.0608 mmol)in H₂O (0.150 mL) was added to the reaction slowly dropwise over 30minutes. After an additional 1.5 hours, the reaction was judged completeby LC-MS analysis. The reaction mixture was partitioned between EtOAcand dilute aq. NaHCO₃. The aqueous phase was washed with EtOAc (×1) andthe combined organic phases were dried over sodium sulfate, filtered,and concentrated. Trituration with diethyl ether provided a white solid(5.0 mg, 22%). MS (ES+) m/e 381 [M+H]⁺.

EXAMPLE 602-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-propionamide

Step 1.2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-propionicacid methyl ester

The ester was prepared from the product of Example 38 (58.0 mg) asdescribed in Example 42, employing methyl 2-bromopropionate as the alkylhalide. The ester was used directly in Step 2. MS (ES+) m/e 381 [M+H]⁺.

Step 2.2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-propionamide

The product of Step 1 was dissolved in methanol (1.0 mL) andconcentrated ammonium hydroxide (0.500 mL) was added. After 14.5 hours,a white precipitate was evident. The reaction mixture was filtered andthe solid washed with water and diethyl ether. The title compound wasisolated as an off-white powder (12.5 mg, 20%). MS (ES+) m/e 366 [M+H]⁺.

The following example was prepared according to the procedure describedin Example 60, Steps 1 and 2.

Example Alkyl Halide 61 2-{4-[2-(4-Amino-furazan-3- Ethyl 2- MS(ES+) m/eyl)-imidazo[4,5-c]pyridin-1-yl]- bromoisobutyrate 366 [M + H]⁺phenoxy}-2-methyl- propionamide

EXAMPLE 62N-(2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-ethyl)-methanesulfonamide

Step 1.4-{1-[4-(2-Bromo-ethoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylaminetrifluoroacetate

The title compound was prepared using the procedure described in example50, using 2-bromoethanol as the alcohol. MS (ES+) m/e 381 [M+H]⁺.

Step 2.N-(2-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-ethyl)-methanesulfonamide

The product of Step 1 (21.5 mg, 0.042 mmol) and methanesulfonamide (8.0mg, 0.080 mmol) were dissolved in DMF. Sodium hydride (60% dispersion inmineral oil, 5.3 mg, 0.133 mmol) was added to the reaction, and themixture was heated to 60° C. After two hours, the reaction was judgedcomplete by LC-MS. The reaction mixture was poured into EtOAc anddiluted with pH 7 phosphate buffer.

The layers were separated and the aqueous layer washed with EtOAc (×3).The combined organic layers were dried over sodium sulfate, filtered,and concentrated. The resulting residue was purified by preparative HPLC(0-80% CH₃CN/H₂O (0.1% TFA), retention time=6.29 minutes) to yield thetitle compound as the trifluoroacetate salt (5.0 mg, 22%). MS (ES+) m/e416 [M+H]⁺.

EXAMPLE 63{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-acetonitrile

To a solution containing 150 mg of the product from Example 38 (0.51mmols) in 2.6 mL of dry DMF was added 25 mg of NaH (0.61 mmols, 60%suspension in oil). After stirring at ambient temperature for 5 min,0.033 mL of chloroacetonitrile (0.51 mmols) was added to the reactionvia syringe. The reaction was warmed to 60° C. for 16 h. After coolingto room temperature, 1 mL of water was carefully added to the reactionmixture. The mixture was diluted with 20 mL of EtOAc and washed with 2NNaOH (3×10 mL). The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was dissolved in a minimum volume ofDMSO and filtered through a 0.45 m acrodisc filter. The resultingsolution was purified on the Gilson reverse-phase HPLC to afford thetitle product (4 mg, 2%). MS (ES+) m/e 334 [M+H]⁺.

The following examples were prepared using the general method of Example63.

alkyl halide or Example alkyl mesylate Characterization 644-{1-[4-(2-Dimethyl (2-chloro-propyl)- MS (ES⁺) m/e amino-1-methyl-dimethyl-amine 380 [M + H]⁺ ethoxy)-phenyl]-1H- imidazo[4,5-c]pyridin-2-yl}- furazan-3-ylamine 65 4-{1-[4-((S)-1- ((S)-1-Methyl- MS(ES⁺) m/e Methyl-pyrrolidin-2- pyrrolidin-2-yl)- 392 [M + H]⁺ylmethoxy)-phenyl]- methyl-mesylate 1H-imidazo[4,5- c]pyridin-2-yl}-furazan-3-yl amine 66 4-(1-{4-[2-(Benzyl- N-(2-chloroethyl)-N- MS (ES⁺)m/e methyl-amino)- methylbenzylamine 442 [M + H]⁺ ethoxy]-phenyl}-1H-hydrochloride imidazo[4,5- c]pyridin-2-yl)- furazan-3-ylamine

EXAMPLE 674-{1-[4-(2-Diethylamino-ethoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine

To a solution containing 50 mg the product from Example 38 (0.17 mmols)in 3.4 mL of dry DMF was added 14 mg of NaH (0.34 mmols, 60% suspensionin oil). After stirring at ambient temperature for 5 min, 44 mg of2-bromoethyl-diethylamine (0.17 mmols) was added to the reaction. Thereaction was warmed to 60° C. for 16 h. After cooling to roomtemperature, 1 mL of water was carefully added to the reaction mixture.The mixture was diluted with 20 mL of EtOAc and washed with 2N NaOH(3×10 mL). The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was dissolved in a minimum volume ofDMSO and filtered through a 0.45 m acrodisc filter. The resultingsolution was purified on the Gilson reverse-phase HPLC. The resultingproduct was dissolved in a minimum amount of MeOH and treated withexcess 1 N HCl in diethylether. The resulting precipitate was collectedand washed with diethylether to afford the title product (11 mg, 17%).MS (ES+) m/e 393 [M]⁺.

The following examples were prepared using the same general method forExample 67.

Example alkyl halide Characterization 68 4-{1-[4-(3-DimethylN-(3-chloropropyl)- MS (ES⁺) m/e amino-propoxy)- dimethylamine 380 [M +H]⁺ phenyl]-1H- imidazo[4,5- c]pyridin-2-yl}- furazan-3-ylamine 694-{1-[4-(3- N-(2-chloroethyl)- MS (ES⁺) m/e Diisopropylamino-diisopropyl-amine 422 [M + H]⁺ ethoxy)-phenyl]-1H- hydrochlorideimidazo[4,5- c]pyridin-2-yl}- furazan-3-ylamine 70 4-{1-[4-(3-N-(2-chloroethyl)- MS (ES⁺) m/e Morpholin-4-yl- morpholine 408 [M + H]⁺ethoxy)-phenyl]-1H- imidazo[4,5- c]pyridin-2-yl}- furazan-3-ylamine 714-{1-[4-(1-Methyl- N-methyl-4-chloro- MS (ES⁺) m/e piperidin-4-yloxy)-piperidine 392 [M + H]⁺ phenyl]-1H- hydrochloride imidazo[4,5-c]pyridin-2-yl}- furazan-3-ylamine 72 4-{1-[4-(2-Piperidin-N-(2-chloroethyl)- MS (ES⁺) m/e 1-yl-ethoxy)- piperidine 406 [M + H]⁺phenyl]-1H- hydrochloride imidazo[4,5- c]pyridin-2-yl}-furazan-3-ylamine

EXAMPLE 734-{1-[4-((S)-1-Pyrrolidin-2-ylmethoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine

This example was prepared using the same general method of Example 67using (S)-(−)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethyl-mesylate (48mg, 23%). MS (ES+) m/e 378 [M+H]⁺.

The following examples were prepared from the product of Example 38using the general method of Example 39

Example Alkyl halide Characterization 74 4-{1-[3-(2-DimethylN-(2-chloro-ethyl)- MS (ES⁺) m/e 366 amino-ethoxy)- dimethyl-amine [M +H]⁺ phenyl]-1H- hydrochloride imidazo[4,5- c]pyridin-2-yl}-furazan-3-ylamine 75 4-{1-[3-(3- N-(2-chloro-propyl)- MS (ES⁺) m/e 380Dimethylamino- dimethyl-amine [M + H]⁺ propoxy)-phenyl]- hydrochloride1H-imidazo[4,5- c]pyridin-2-yl}- furazan-3-ylamine

EXAMPLE 764-{1-[4-(3-Methyl-butoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine

The title compound was prepared using the same general method forExample 50 starting from isoamyl alcohol. MS (ES+) m/e 364 [M+H]⁺.

EXAMPLE 774-{1-[3-(1-Methyl-piperidin-4-yloxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine

The title compound was prepared from the product of Example 39 using thegeneral method of Example 50 using N-methyl-4-hydroxy-piperidine. MS(ES+) m/e 392 [M+H]⁺.

EXAMPLE 78N-{4-[2-(4-Amino-furazan-3-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-phenyl}-N′,N′-dimethyl-ethane-1,2-diamine

Step 1.4-[1-(4-Amino-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The title compound was prepared by the method of Example 25 startingfrom 4-chloro-3-nitro pyridine and (4-aminophenyl)-carbamic acid t-butylester. MS (ES+) m/e 294 [M+H]⁺.

Step 2.N-{4-[2-(4-Amino-furazan-3-yl)-1H-imidazo[4,5-c]pyridin-1-yl]-phenyl}-N′,N′-dimethyl-ethane-1,2-diamine

To a solution containing 500 mg the product from Step 1 (1.7 mmol) in 10mL DMF was added 200 mg of NaH (60% dispension in oil, 5.1 mmol). After2 hours at room temperature, 246 mg of 2-(dimethylamino)ethyl chloridehydrochloride (1.7 mmol) was added, and the reaction mixture was heatedto 60° C. for 5 hours. The solvent was evaporated in vacuo to yield aresidue which was partitioned between ethyl acetate and brine. Theorganic phase was dried over anhydrous sodium sulphate, filtered, andconcentrated in vacuo. Purification of the residue by Gilsonreverse-phase HPLC afforded the title compound (24 mg, 4%). MS (ES⁺) m/e365 [M+H]⁺.

EXAMPLE 791-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-3-methyl-urea

To a solution containing 50 mg the product from Example 78, Step 1 (0.17mmol) in 1 mL pyridine, was added 20 mg of methyl isocyanate (0.34 mmol)dropwise at 0° C. The resulting mixture was stirred at room temperaturefor 5 hours. The solvent was evaporated in vacuo to yield a residuewhich was partitioned between ethyl acetate and brine. The organic phasewas dried over anhydrous sodium sulphate, filtered, and concentrated invacuo. Purification of the residue by Gilson reverse-phase HPLC affordedthe title compound (5.4 mg, 9.0%). MS (ES+) m/e 351 [M+H]⁺.

EXAMPLE 80N-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-C-dimethylamino-acetamide

To a solution containing 100 mg of the product of Example 78, Step 1(0.3 mmol) in 5 mL CH₂Cl₂, was added 65 mg of dimethylamino acetylchloride (0.4 mmol) and 92 mg of triethylamine (0.9 mmol). The resultingmixture was heated to reflux for 12 hours. The reaction was cooled toambient temperature and the solvent was concentrated in vacuo. Theresulting residue was partitioned between ethyl acetate and brine. Theorganic phase was dried over anhydrous sodium sulphate, filtered, andconcentrated in vacuo. Purification of the residue by Gilsonreverse-phase HPLC afforded the title compound (38 mg, 30%). MS (ES+)m/e 379 [M+H]⁺.

The following examples were prepared using the general method of Example30

Example Aniline Characterization 81 4-[1-(1H-Indazol-5- 5-amino-indazoleMS (ES⁺) m/e 319 yl)-1H-imidazo[4,5- [M + H]⁺ c]pyridin-2-yl]-furazan-3-ylamine 82 4-[1-(1H-Indazol-6- 6-amino-indazole MS (ES⁺) m/e319 yl)-1H-imidazo[4,5- [M + H]⁺ c]pyridin-2-yl]- furazan-3-ylamine 834-{1-[4-(3- 4-(3-dimethylamino MS (ES⁺) m/e 364 Dimethylamino-propyl)aniline (Klein, [M + H]⁺ propyl)-phenyl]-1H- C. D. P.;imidazo[4,5- Klingmueller, M.; c]pyridin-2-yl}- Schellinski, C.;furazan-3-ylamine Landmann, S.; Hauschild, S.; Heber, D.; Mohr, K.;Hopfinger, A. J. J. Med. Chem. 1999, 42, 3874-3888. 84 4-[1-(4-N,N-Dimethyl- MS (ES⁺) m/e 322 Dimethylamino- benzene-1,4- [M + H]⁺phenyl)-1H- diamine (Wurster; imidazo[4,5- Chem. Ber. 1879,c]pyridin-2-yl]- 12, 523.) furazan-3-ylamine 85 4-(1-enzo[1,3]dioxol-benzo [1,3]dioxol-5- MS (ES⁺) m/e 323 5-yl-1H- ylamine [M + H]⁺imidazo[4,5- c]pyridin-2-yl) furazan-3-ylamine 86 4-[1-(2-Methyl-2-methyl-1,2,3,4- MS (ES⁺) m/e 348 1,2,3,4-tetrahydro- tetrahydro- [M +H]⁺ isoquinolin-7-yl)-1H- isoquinolin-7- imidazo[4,5- ylamine (Heer, J.P.; c]pyridin-2-yl]- Harling, John D.; furazan-3-ylamine Thompson,Mervyn. Synthetic Communications 2002, 32(16), 2555- 2563.) 871-{4-[2-(4-Amino- 4-amino- MS (ES⁺) m/e 336 furazan-3-yl)- acetophenone[M + H]⁺ imidazo[4,5- c]pyridin-1-yl]- phenyl}-ethanone oxime 884-[1-(2,3,4,5- 2,3,4,5-tetrahydro-1 MS (ES⁺) m/e 348 Tetrahydro-1H-H-benzo[c]azepin- [M + H]⁺ benzo[c]azepin-8- 8-ylamineyl)-1H-imidazo[4,5- (Grunewald, G. L.; c]pyridin-2-yl]- Dahanukar, V.H.; furazan-3-ylamine Criscione, K. R. Bioorganic & Medicinal Chemistry2001, 1957-1965.) 89 7-[2-(4-Amino- 7-amino-3,4- MS (ES⁺) m/e 348furazan-3-yl)- dihydro-2H- [M + H]⁺ imidazo[4,5- isoquinolin-1-onec]pyridin-1-yl]-3,4- (Lee, N-H.; Lee, C- dihydro-2H- S.; Jung, D-S.isoquinolin-1-one Tetrahedron Lett. 1998, 39, 1385- 1388.) 904-[2-(4-Amino- 4-amino-benzonitrile MS (ES+) m/e 337 furazan-3-yl)- [M +H]⁺ imidazo[4,5- c]pyridin-1-yl]-N- hydroxy- benzamidine

EXAMPLE 91N-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-N,N′,N′-trimethyl-ethane-1,2-diamine

Step 1: N,N, N′-Trimethyl-N′-(4-nitro-phenyl)-ethane-1,2-diamine

To a solution containing 1.52 g of 4-nitro-N-methylaniline (10 mmol) in30 mL THF, was added 0.8 g of sodium hydride (60% dispension in oil, 20mmol). After 5 minutes at room temperature, 2.59 g of2-(dimethylamino)ethyl chloride hydrochloride (18 mmol) and 0.4 g ofsodium hydride (60% dispension in oil, 10 mmol) were added. The reactionwas heated at 60° C. for 5 hours. The solvent was concentrated in vacuoto yield a residue which was partitioned between ethyl acetate and 2 Msodium hydroxide solution. The organic phase was washed with water (3×),dried over anhydrous sodium sulphate, filtered, and concentrated invacuo to yield the title compound as a brown oil (1.23 g, 55%). MS (ES⁺)m/e 224 [M+H]⁺.

Step 2: N-(2-dimethylaminoethyl)-N-methyl-benzene-1,4-diamine

To a solution containing 1.23 g of product from step 1 (5.5 mmol) in 20mL MeOH, was added 0.6 g of Pd (5 wt. % on activated carbon). Theresulting suspension was stirred under H₂ (50 psi) at room temperaturefor 3 hours. The reaction mixture was filtered through celite. Thefiltrate was concentrated in vacuo to yield the title compound as acolorless oil (0.71 g, 67%). MS (ES⁺) m/e 194 [M+H]⁺.

Step 3:N-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-N,N′,N′-trimethyl-ethane-1,2-diamine

This example was prepared using the general method of Example 30 usingthe product from step 2. MS (ES+) m/e 379 [M+H]⁺.

EXAMPLE 92N-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

Step 1:N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-N-(4-nitro-phenyl)-ethane-1,2-diamine

To a solution containing 2.76 g of 4-nitroaniline (20 mmol) in 20 mL DMFwas added 1.60 g of NaH (60% dispension in oil, 40 mmol). After 2 hoursat room temperature, 2-(dimethylamino)ethyl chloride hydrochloride (3.46g, 24 mmol) was added, and the reaction mixture was heated at 60° C. for12 hours. The solvent was evaporated in vacuo to yield a residue whichwas partitioned between ethyl acetate and brine. The organic phase wasdried over anhydrous sodium sulphate, filtered, and concentrated invacuo to yield a residue. Purification of the residue by flashchromatography with 2% MeOH in CH₂Cl₂ as the eluent yieldedN,N-dimethyl-N′-(4-nitro-phenyl)-ethane-1,2-diamine (2.34 g, 56%) andthe title compound (1.23 g, 22%). MS (ES+) m/e 281 [M+H]⁺.

Step 2: N,N-bis-(2-dimethylamino-ethyl)-benzene-1,4-diamine

To a solution containing 1.23 g of product from step 1 (4 mmol) in 20 mLMeOH, was added 0.8 g of Pd (5 wt. % on activated carbon, 0.4 mmol). Theresulting suspension was stirred under H₂ (50 psi) at room temperaturefor 3 hours. The reaction mixture was filtered, and the filtrate wasconcentrated in vacuo to yield the title compound as a colorless oil(1.10 g, 100%). MS (ES+) m/e 251 [M+H]⁺.

Step 3:N-{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-N-(2-dimethylamino-ethyl)-N′,N′-dimethyl-ethane-1,2-diamine

This example was prepared using the general method of Example 30 usingthe product from step 2. MS (ES+) m/e 436 [M+H]⁺.

EXAMPLE 93N-(2-{4-[2-(4-amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenoxy}-ethyl)-benzenesulfonamide

The product of example 55 was suspended in dichloromethane (1.25 mL) andtriethylamine (0.218 mL, 0.487 mmol) was added, followed bybenzenesulfonyl chloride (0.023 mL, 0.182 mmol). After 30 minutes, thereaction mixture was partitioned between ethyl acetate and 2N NaOH. Theaqueous phase was washed with ethyl acetate (×1). The combined organicphases were washed with satd. aq. NaCl, dried over sodium sulfate,filtered and concentrated. The resulting residue was purified bypreparative HPLC (0-80% CH₃CN/H₂O (0.1% TFA), retention time=7.31minutes) to yield the title compound as the trifluoroacetate salt (25.7mg, 44%). MS (ES+) m/e 478 [M+H]⁺.

EXAMPLE 944-[1-(4-Aminomethyl-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

Step 1:{4-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-benzyl}-carbamicacid tert-butyl ester

The title compound was prepared from (4-aminobenzyl)-carbamic acidtert-butyl ester (J. Am. Chem. Soc, 112, 12, 2000, 2698-2710), using theprocedures detailed in Example 30; MS (ES+), m/e 408 [M+H]⁺.

Step 2:4-[1-(4-Aminomethyl-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The title compound was prepared from the product of Step 1 using themethod of Example 21; MS (ES+), m/e 308 [M+H]⁺.

The following examples were prepared using the general two step methodof example 94.

Example Aniline Characterisation 95 4-[1-(3-Aminomethyl-(3-Amino-benzyl)- MS (ES+) m/e phenyl)-1H- carbamic acid tert- 308 [M +H]⁺ imidazo[4,5- butyl ester. (J. c]pyridin-2-yl]- Med. Chem. 42,furazan-3-ylamine 14, 1999, 2504- 2526) 96 4-[1-(1,2,3,4-Tetrahydro-5-Amino-3,4- MS (ES+) m/e isoquinolin-5-yl)-1H- dihydro-1H- 334 [M + H]⁺imidazo[4,5- isoquinoline-2- c]pyridin-2-yl]- carboxylic acidfurazan-3-ylamine tert-butyl ester. (Bioorg. Med. Chem. 8, 8, 2000,2085-2094). 97 4-[1-(1,2,3,4-Tetrahydro- 7-Amino-3,4- MS (ES+) m/eisoquinolin-7-yl)-1H- dihydro-1H- 334 [M + H]⁺ imidazo[4,5-isoquinoline-2- c]pyridin-2-yl]- carboxylic acid furazan-3-ylaminetert-butyl ester (WO 99/14197)

EXAMPLE 984-[1-(2,3-Dihydro-1H-isoindol-5-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

Step 1: 5-nitroisoindoline Nitrate

Isoindoline (4 g, 33.1 mmol) was added to 95%. sulphuric acid, thereaction was treated carefully with fuming nitric acid (2.2 ml) at 0° C.and stirred for 1 hour, then the mixture was poured onto ice and theresulting precipitate was collected by filtration and dried in vacuo toafford the title compound (4.1 g, 46%); 1H NMR (DMSO-d6) 8.35 (1H, s),8.35 (1H, d, 8.4 Hz), 7.70 (1H, d, 8.4 Hz), 4.64 (4H, s).

Step 2: 5-Nitro-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

The product of Step 1 (3.06 g, 13.47 mmol) in dichloromethane (50 ml)was treated with triethylamine (4.09 g, 40.42 mmol) followed bydi-tertbutyl dicarbonate (3.08 g, 14.15 mmol) and stirred at roomtemperature for 3 days. The reaction was then diluted withdichloromethane and washed with 3N citric acid, sodium bicarbonatesolution, water and brine. The organic phase was separated, dried overanhydrous sodium sulfate and evaporated in vacuo to afford the titlecompound (3.5 g, 98%); 1H NMR (CDCl3) 8.19 (2H, m), 7.26 (1H, m), 4.75(4H, m), 1.52 (9H, s).

Step 3: 5-Amino-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

The product of Step 2 (3.5 g, 13.25 mmol) was dissolved in ethanol (200ml) and treated with 10 wt % Palladium on charcoal (1 g), and stirredunder 1 atm of H₂ for 16 hours. The reaction was filtered and evaporatedin vacuo to afford the title compound (3.01 g, 96%); MS (ES+), m/e 235[M+H]⁺.

Step 4:4-[1-(2,3-Dihydro-1H-isoindol-5-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The amine from Step 3 was reacted according to the general two stepmethod of Example 94 to give the title product. MS (ES+) m/e 320 [M+H]⁺.

EXAMPLE 994-[1-(3-Pyrrolidin-2-yl-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

Step 1: 2-(3-Nitro-phenyl)-pyrrole-1-carboxylic acid tert-butyl ester

A solution of 1-bromo-3-nitrobenzene (1.5 g 7.42 mmol) in anhydrous1,2-dimethoxyethane (10 ml) was treated sequentially with1,1-bistriphenylphosphine palladium II dichloride (260 mg, 0.371 mmol),2M aqueous sodium carbonate (7.4 ml), and1-(t-Butoxycarbonyl)pyrrole-2-boronic acid (1.88 g, 8.91 mmol) dissolvedin ethanol (10 ml). The reaction was heated under reflux for 5 hoursunder argon. The solvent was evaporated and the residue dissolved indichloromethane, washed with water, brine, dried over anhydrous sodiumsulfate, and evaporated in vacuo. The residue was purified by silica gelchromatography eluting with a mixture of ether/hexane (5:95) to affordthe title compound (1.09 g, 51%); MS (ES+) m/e 288 [M+H]⁺.

Step 2: 2-(3-Amino-phenyl)-pyrrolidine-1-carboxylic acid tert-butylester

The product of Step 1 (7.5 g, 26.01 mmol), was dissolved in ethanol (125ml), and treated with 5 wt % Platinum on charcoal (750 mg), and stirredunder 1 atm of H₂ for 4 days. The reaction was filtered and the filtrateevaporated in vacuo. The residue was purified by silica gelchromatography eluting with a mixture of ether/dichloromethane (5:95) toafford the title compound (4.2 g, 62%); MS (ES+) m/e 263 [M+H]⁺.

Step 3:2-{3-[2-(4-Amino-furazan-3-yl)-imidazo[4,5-c]pyridin-1-yl]-phenyl}-pyrrolidine-1-carboxylicacid tert-butyl ester

The title compound was prepared from the product of Step 2 using themethods of example 30; MS (ES+), m/e 448 [M+H]⁺.

Step 4:4-[1-(3-Pyrrolidin-2-yl-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The title compound was prepared from the product of Step 3 using themethod of Example 21; MS (ES+), m/e 348 (M+H]⁺.

EXAMPLE 1004-(7-Bromo-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

Step 1. (3-Bromo-5-nitropyridin-4-yl)ethylamine

To a solution of the product of Example 1 Step 1 (3.0 g, 17.9 mmol) inacetic acid (40 ml) was added bromine (3.12 g, 1 ml, 19.7 mmol) and themixture was heated at 100° C. for 20 hours. After cooling the solventwas removed in vacuo and the residue was partitioned betweendichloromethane and saturated sodium bicarbonate solution. The organicphase was washed with water (×3), dried and evaporated in vacuo.Purification of the residue by silica gel chromatography eluting with50% dichloromethane in ethyl acetate afforded the title compound (1.9 g,43%). ¹H NMR (DMSO-d₆) 8.73 (1H, s), 8.52 (1H, s), 7.0 (1H, br), 3.25(2H, m), 1.16 (3H, t, J=7.2 Hz).

Step 2. 5-Bromo-N⁴-Ethylpyridine-3,4-diamine

A solution of the product of Step 1 (0.5 g, 2 mmol) in ethanol (8ml)/water (10 ml) was stirred at 60° C. and sodium dithionite (2.12 g,12.2 mmol) was added protionwise. After 10 minutes the mixture wascooled to room temperature, and diluted with water and dichloromethane.The organic phase was dried and evaporated in vacuo, the residue wasused directly in the next reaction; ¹H NMR (DMSO-d₆) 7.76 (1H, s), 7.75(1H, s), 5.0 (2H, br), 4.46 (1H, t, J=9.6 Hz), 3.26 (2H, m), 1.06 (3H,t, J=7.2 Hz).

Step 3.4-(7-Bromo-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

The title compound was prepared from the product of Step 2 using themethods of Example 1 Steps 3 and 4; MH (ES+) m/e 309/311 [M+H]⁺.

EXAMPLE 1014-(1-Ethyl-7-phenyl-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

A mixture of the product of Example 100 (50 mg, 0.161 mmol),phenylboronic acid (30 mg, 0.243 mmol),bis(triphenylphosphine)palladium(II) dichloride (11 mg, 0.0161 mmol),sodium carbonate solution (2M, 0.25 ml) and toluene (3 ml) was heated at100° C. for 3 hours.

After cooling to room temperature the solvent was evaporated in vacuoand the residue purified by silica gel chromatography eluting with 50%dichloromethane in ethyl acetate to afford the title compound; (45 mg,92%). MS (ES+) m/e 307 [M+H]⁺.

The following examples were prepared by the general method described inExample 101.

Example Boronic acid Characterisation 102 4-[1-Ethyl-7-(4-4-Methoxyphenylboronic MS(ES+) m/e methoxyphenyl)-1H- acid 337 [M + H]⁺imidazo[4,5-c]pyridin-2- yl]furazan-3-ylamine 1034-(1-Ethyl-7-thiophen-2-yl-1H- Thiophene-2-boronic MS (ES+) m/eimidazo[4,5-c]pyridin-2- acid 313 [M + H]⁺. yl)furazan-3-ylamine

The following example was prepared by the general method described inExample 101, replacing the toluene solvent by 1,2-dimethoxyethane.

104 4-[7-(4- 4-(Aminomethyl)- MS (AP+) m/e Aminomethylphenyl)-phenylboronic acid 336 [M + H]⁺. 1-ethyl-1H- imidazo[4,5- c]pyridin-2-hydrochloride yl]furazan-3- ylamine

The following example was prepared by the general method described inExample 101, replacing the toluene solvent by dioxane.

Example Boronic Acid Characterization 105 4-[7-(3-Ethoxy-phenyl)-1-3-Ethoxyphenylboronic MS (ES+) m/e 351 ethyl-1H-imidazo[4,5- acid [M +H]⁺ c]pyridin-2-yl]-furazan-3- ylamine 1064-[1-Ethyl-7-(2-fluoro-phenyl)- 2-Fluorophenylboronic MS (ES+) m/e 3251H-imidazo[4,5-c]pyridin-2- acid [M + H]⁺ yl]-furazan-3-ylamine 1074-[1-Ethyl-7-(4- 4-(Methanesulfonyl)benzene- MS (ES+) m/e 385methanesulfonyl-phenyl)-1H- [M + H]⁺ imidazo[4,5-c]pyridin-2-yl]-boronic acid furazan-3-ylamine 108 4-[1-Ethyl-7-(4-4-Trifluoromethylbenzene- MS (ES+) m/e 375 trifluoromethyl-phenyl)-1H -boronic acid [M + H]⁺ imidazo[4,5-c]pyridin-2-yl]- furazan-3-ylamine 1094-[7-(2,4-Difluoro-phenyl)-1- 2,4-Difluorophenylboronic MS (ES+) m/e 343ethyl-1H-imidazo[4,5- acid [M + H]⁺ c]pyridin-2-yl]-furazan-3- ylamine110 4-[1-Ethyl-7-(2- 2-Trifluoromethylbenzene- MS (ES+) m/e 375trifluoromethyl-phenyl)-1H- boronic acid [M + H]⁺imidazo[4,5-c]pyridin-2-yl]- furazan-3-ylamine 111 4-[1-Ethyl-7-(4-4-(Methylthio)benzeneboronic MS (ES+) m/e 353 methylsulfanyl-phenyl)-1H-acid [M + H]⁺ imidazo[4,5-c]pyridin-2-yl]- furazan-3-ylamine 1124-[7-(2,6-Dimethyl-phenyl)-1- 2,6-Dimethylphenylboronic MS (ES+) m/e 335ethyl-1H-imidazo[4,5- acid [M + H]⁺ c]pyridin-2-yl]-furazan-3- ylamine113 5-[2-(4-Amino-furazan-3-yl)-1- 4-Fluoro-3- MS (ES+) m/e 353ethyl-1H-imidazo[4,5- formylbenzeneboronic [M + H]⁺c]pyridin-7-yl]-2-fluoro- acid benzaldehyde 114 4-[7-(3-Amino-phenyl)-1-3-Aminobenzeneboronic MS (ES+) m/e 322 ethyl-1H-imidazo[4,5- acidmonohydrate [M + H]⁺ c]pyridin-2-yl]-furazan-3- ylamine 1154-[1-Ethyl-7-(3- 3-(Trifluoromethoxy)phenyl- MS (ES+) m/e 391trifluoromethoxy-phenyl)-1H- boronic acid [M + H]⁺imidazo[4,5-c]pyridin-2-yl]- furazan-3-ylamine 1161-{3-[2-(4-Amino-furazan-3- 3-Acetylphenylboronic MS (ES+) m/e 349yl)-1-ethyl-1H-imidazo[4,5-c] acid [M + H]⁺pyridin-7-yl]-phenyl}-ethanone 117 N-}4-[2-(4-Amino-furazan-3- [(4- MS(ES+) m/e 400 yl)-1-ethyl-1H-imidazo[4,5-c] Methylsulfonyl)amino- [M +H]⁺ pyridin-7-yl]-phenyl}- phenyl]boronic acid methanesulfonamide 1184-[(Bis-trifluoromethyl- 3,5-Bis(trifluoromethyl)- MS (ES+) m/e 443phenyl)-ethyl-1H- benzeneboronic acid [M + H]⁺imidazo[4,5-c]pyridin-2-yl]- furazan-3-ylamine 1194-[2-(4-Amino-furazan-3-yl)-1- 3-Fluoro-4- MS (ES+) m/e 353ethyl-1H-imidazo[4,5- formylbenzeneboronic [M + H]⁺c]pyridin-7-yl]-2-fluoro- acid benzaldehyde

EXAMPLE 1204-[1-Ethyl-7-(4-methanesulfinyl-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

A solution of the product from Example 111 (0.030 g, 0.085 mmol) indichloromethane (4 mL), was cooled to −78° C. under Argon, and wastreated with mCPBA (0.029 g, 0.17 mmol). Allowed the reaction mixture towarm to room temperature and stir for 6 hours. The reaction was reducedin-vacuo, then was dissolved in DMSO (1 mL), and purified on the Gilsonvia reverse-phase HPLC to afford the title compound (12 mg, 38%); MS(ES+) m/e 369 [M+H]⁺.

The following example was prepared by the general method described inExample 101, replacing the toluene solvent by DMF.

Example Boronic Acid Characterization 121 5-[2-(4-Amino-furazan-3-yl)-1-5-Formyl-2- MS (ES+) m/e 355 ethyl-1H-imidazo[4,5- thiopheneboronic acid[M + H]⁺ c]pyridin-7-yl]-thiophen-2-yl}- carbaldehyde 1224-(7-Benzo[b]thiophen-3-yl- Benzothiophene-3- MS (ES+) m/e 3631-ethyl-1H-imidazo[4,5- boronic acid [M + H]⁺ c]pyridin-2-yl]-furazan-3-ylamine 123 4-[1-Ethyl-7-(4-methyl- 4-Methylthiophene-2- MS (ES+) m/e327 thiophen-2-yl)-1H- boronic acid [M + H]⁺imidazo[4,5-c]pyridin-2-yl]- furazan-3-ylamine 1244-[1-Ethyl-7-(5-phenyl- 5-Phenylthiophene-2- MS (ES+) m/ethiophen-2-yl)-1H- boronic acid 389 imidazo[4,5-c]pyridin-2-yl]- [M +H]⁺ furazan-3-ylamine

The following examples were prepared by the general method described inExample 101, replacing the toluene solvent by 1,2-dimethoxyethane, andpalladium bis(triphenylphosphine)palladium(II) dichloride catalyst withtetrakis(triphenylphosphine)palladium(0).

125 4-(7-Benzo[1,3]dioxol-5-yl-1- 3,4-Methylenedioxy MS (ES+) m/eethyl-1H-imidazo[4,5- phenyl boronic acid 351 [M + H]⁺.c]pyridin-2-yl)furazan-3- ylamine 126 4-(1-Ethyl-7-pyridin-4-yl-1H-4-Pyridylboronic acid MS (ES+) m/e 308 imidazo[4,5-c]pyridin-2- [M +H]⁺. yl)furazan-3-ylamine 127 4-(1-Ethyl-7-pyridin-3-yl-1H-3-Pyridylboronic acid MS (ES+) m/e 308 imidazo[4,5-c]pyridin-2- [M +H]⁺. yl)furazan-3-ylamine 128 4-(1-Ethyl-7-furan-3-yl-1H- 3-Furylboronicacid MS (ES+) m/e297 imidazo[4,5-c]pyridin-2- [M + H]⁺.yl)furazan-3-ylamine 129 4-(1-Ethyl-7-thiophen-3-yl-1H-3-Thiopheneboronic acid MS (ES+) m/e 313 imidazo[4,5-c]pyridin-2- [M +H]⁺. yl)furazan-3-ylamine 130 4-[1-Ethyl-7-(4-phenoxy- 4-Phenoxybenzene-MS (ES+) m/e 399 phenyl)-1H-imidazo[4,5- boronic acid [M + H]⁺.c]pyridin-2-yl]furazan-3- ylamine 131 4-(1-Ethyl-7-quinoline-8-yl-8-Quinoline boronic acid MS (ES+) m/e 1H-imidazo[4,5-c]pyridin-2- 358[M + H]⁺. yl]furazan-3-ylamine 132 4-[7-(3,5-Dimethyl-isoxazole-4-(3,5-Dimethylisoxazole) MS (ES+) m/e 4-yl)-1-ethyl-1H-imidazo[4,5-boronic acid 326 [M + H]⁺. c]pyridin-2-yl]furazan-3- ylamine 1334-[1-Ethyl-7-(4-fluoro-phenyl)- 4-Fluorobenzene boronic MS (ES+) m/e1H-imidazo[4,5-c]pyridin-2- 346 [M + H]⁺. yl]furazan-3-ylamine 1344-[1-Ethyl-7-(4-indol-5-yl-)-1 5-Indolylboronic acid MS (ES+) m/eH-imidazo[4,5-c]pyridin-2- acid 325 [M + H]⁺. yl]furazan-3-ylamine 1353-[2-(4-Amino-furazan-3-yl)-1- 3-Cyanophenyl boronic MS (ES+) m/eethyl-1-H- acid 332 [M + H]⁺. imidazo[4,5,c]pyridin-7-yl]- benzonitrile136 4-[2-(4-Amino-furazan-3-yl)-1- 4-Hydroxyphenyl boronic MS (ES+) m/eethyl-1-H- acid 323 [M + H]⁺. imidazo[4,5,c]pyridin-7-yl]- phenol 137N-{3-[2-(4-Amino-furazan-3- 3-Acetamidophenyl MS (ES+) m/eyl)-1-ethyl-1-H- boronic acid 364 [M + H]⁺. imidazo[4,5,c]pyridin-7-yl]-phenyl}-acetamide 138 4-[2-(4-Amino-furazan-3-yl)-1- 4-Cyanophenylboronic MS (ES+) m/e ethyl-1-H- acid 332 [M + H]⁺.imidazo[4,5,c]pyridin-7-yl]- benzonitrile 139 4-[1-Ethyl-7-(3-3-Trifluoromethylphenyl MS (ES+) m/e trifluoromethyl-phenyl)-1H- boronicacid 375 [M + H]⁺. imidazo[4,5-c]pyridin-2- yl)furazan-3-ylamine 140{3-[2-(4-Amino-furazan-3-yl)- (3-Hydroxymethyl) MS (ES+) m/e1-ethyl-1-H- phenyl boronic acid 337 [M + H]⁺.imidazo[4,5,c]pyridin-7-yl]- phenyl}-methanol 1413-[2-(4-Amino-furazan-3-yl)-1- N,N-Dimethylbenzamide- MS (ES+) m/eethyl-1-H- 3-boronic acid 378 [M + H]⁺. imidazo[4,5,c]pyridin-7-yl]-N,N-dimethyl-benzamide 142 4-{1-Ethyl-7-[4-(5-methyl- 4-(5-Methyl- MS(ES+) m/e [1,2,4]Oxadiazole-3-yl)- [1,2,4]Oxadiazol-3- 389 [M + H]⁺.phenyl]-1H-imidazo[4,5- yl)benzene boronic acidc]pyridin-2-yl]furazan-3- [prepared from the ylamine correspondingbromide (WO9743262) using the general procedure of Bagley et alTetrahedron Lett. 2000, 41(35), 6901.] 1434-[2-(4-Amino-furazan-3-yl)-1- 4-Aminocarbonylphenyl MS (ES+) m/eethyl-1-H- boronic acid 350 [M + H]⁺. imidazo[4,5,c]pyridin-7-yl]-benzamide 144 3-[2-(4-Amino-furazan-3-yl)-1- 3-Aminocarbonylphenyl MS(ES+) m/e ethyl-1-H- boronic acid 350 [M + H]⁺.imidazo[4,5,c]pyridin-7-yl]- benzamide 145 4-{7-[4-(2-Amino-ethyl)-4-(2-Amino-ethyl)- MS (ES+) m/e phenyl]-1-ethyl-1H- benzene boronic acid350 [M + H]⁺. imidazo[4,5-c]pyridin-2- (WO9910022) yl]furazan-3-ylamine146 4-[7-(3-aminomethyl-phenyl)- 3-Aminomethyl-phenyl MS (ES+) m/e1-ethyl-1H-imidazo[4,5- boronic acid 336 [M + H]⁺c]pryridin-2-yl]-furazan-3- ylamine 147 4-(1-ethyl-7-o-tolyl-1H-2-Methylphenyl boronic MS (ES+) m/e imidazo[4,5]pryidin-2-yl- acid 322[M + H]⁺ furazan-3-ylamine

The following example was prepared by the general method described inExample 101, replacing the toluene solvent by N,N-dimethylformamide andreplacing bis(triphenylphosphine)palladium(II) dichloride with1,1′-bis(diphenylphoshino)ferrocenedichloropalladium(II) chloroformcomplex.

148 4-[2-(4-Amino-furazan- 4-Formyl phenyl MS (ES+) m/e 3353-yl)-1-ethyl-1H- boronic acid [M + H]⁺ imidazo[4,5-c]pryidin-7-yl]-benzaldehyde

EXAMPLE 1494-[1-Ethyl-7-(4-morpholin-4-ylmethyl-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

To a solution of the product of Example 148 (65 mg, 0.19 mmol) inmethanol (5 ml) was added morpholine (33 mg, 0.033 ml, 0.38 mmol),acetic acid (0.2 ml) and (polystyrylmethyl)trimethylammoniumcyanoborohydride (94 mg, 0.38 mmol). This mixture was stirred for 18hours. The (polystyrylmethyl)trimethylammonium cyanoborohydride wasfiltered off and the residue concentrated in vacuo. The residue waspurified by silica gel chromatography eluting with DCM:methanol (40:1)to afford the title compound (21 mg, 13%); MS (ES+) m/e 406 [M+H]⁺.

The following compounds were prepared by the general method described inExample 149 from the product of Example 148.

Example Amine Characterisation 150 4-[1 Ethyl-7-(4- Ethylamine in MS(ES+) m/e ethylaminomethyl- THF (1M) 364 [M + H]⁺ phenyl)-1H-imidazo[4,5- c]pyridin-2- yl]furazan-3-ylamine 151 4-{4-[2-(4-Amino-4-Amino-piperidine- MS (ES+) m/e furazan-3-yl)-1-ethyl-1H- 1-carboxylicacid 519 [M + H]⁺ imidazo[4,5-c]pyridin- tert-butyl ester7-yl]-benzylamino}- piperidine-1-carboxylic acid tert-butyl ester 1524-[1-Ethyl-7-(4- Pyrrolidine MS (ES+) m/e pyrrolidin-1-ylmethyl- 390[M + H]⁺ phenyl)-1H-imidazo[4,5- c]pyridin-2-yl]- furazan-3-ylamine

EXAMPLE 153 4-[1Ethyl-7-(3-ethylaminomethyl-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]furazan-3-ylamine

Step 1:3-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pryidin-7-yl]-benzaldehyde

The crude title compound was prepared from the 3-formylphenyl boronicacid using the method of Example 148.

Step 2: 4-[1Ethyl-7-(3-ethylaminomethyl-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]furazan-3-ylamine

The product of Step 1 was converted into the title compound by reactionwith ethylamine (1M in THF) according to the general method of Example149. MS (ES+) m/e 364 [M+H]⁺.

The following compounds were prepared by the general method described inExample 149 from the product of Example 153 Step 1.

Example Amine used Characterisation 154 4-[7-(3- Dimethylamine MS(ES+)m/e Dimethylaminomethyl- 365 [M + H]⁺ phenyl)-1-ethyl-1H-imidazo[4,5-c]pyridin- 2-yl]-furazan-3-ylamine 1554-[1-ethyl-7-(3-morpholin- Morpholine MS (ES+) m/e 4-ylmethyl- 406 [M +H]⁺ phenyl)-1 H-imidazo[4,5- c]pyridin-2-yl]- furazan-3-ylamine 1564-[1-Ethyl-7-(3- Pyrrolidine MS (ES+) m/e pyrrolidin-1-ylmethyl- 390[M + H]⁺ phenyl)-1H-imidazo[4,5- c]pyridin-2-yl]- furazan-3-ylamine

EXAMPLE 157{4-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-benzyl}-piperidin-4-yl-amine

The title compound was prepared from the product of Example 151 usingthe method described in Example 21; MS (ES+) m/e 419 [M+H]⁺.

EXAMPLE 158{3-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-benzyl}-piperidin-4-yl-amine

The title compound was prepared from 4-amino-piperidine-1-carboxylicacid tert-butyl ester and the product of Example 153 Step 1 using themethod of Example 149, followed by the method described in Example 21.MS (ES+) m/e 419 [M+H]⁺.

EXAMPLE 1594-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-benzoicAcid

To a solution of the product from Example 100 (1.5 g, 4.85 mmol) in1,4-Dioxane (50 ml) was added 4-carboxybenzene boronic acid (1.20 g,7.23 mmol), sodium carbonate (7 ml of a 2 M solution) andtetrakis(triphenylphosphine)palladium(0) (1.12 g, 0.97 mmol). Thereaction mixture was heated to reflux with stirring for 18 hours andallowed to cool. The reaction mixture was filetered and washed withether (5×, 100 ml) to afford the title compound as a yellow solid (0.594g, 35%); MS (ES+) m/e 351 [M+H]⁺.

The following example was prepared by the method of Example 159

Example Boronic acid Characterisation 160 3-[2-(4-Amino-3-carboxybenzene MS (ES+) m/e furazan-3-yl)-1- boronic acid 351 [M +H]⁺. ethyl-1H-imidazo[4,5- c]pyridin-7- yl]-benzoic acid

EXAMPLE 1614-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-]pyridin-7-yl]-phenyl}-1-morpholin-4-yl-methanone

The product from Example 159 in DMF (5 ml) (0.200 g, 571 mmol) wastreated with PyBop (892 mg, 1.71 mmol), DIPEA (297 ul, 1.71 mmol) andmorpholine (149 ul, 1.71 mmol). The mixture was stirred at roomtemperature for 18 hours and the crude product concentrated to a glassysolid. The crude product was purified on a Gilson HPLC system to yieldthe titled compound as a solid (0.129 g, 54%); MS (ES+) m/e 420 [M+H]⁺.

The following compounds were prepared by the general method described inExample 161 from the product of Example 159.

Example Amine Characterisation 162 4-[2-(4-Amino- phenethyl amine MS(ES+) m/e furazan-3-yl)-1- 454 [M + H]⁺ ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-N- phenethyl-benzamide 163 4-[2-(4-Amino-furazan-Pyrroliidine MS (ES+) m/e 3-yl)-1-ethyl-1H- 404 [M + H]⁺imidazo[4,5-]pyridin- 7-yl]-phenyl}-1- pyrrolidin-1-yl- methanone 1644-[2-(4-Amino-furazan- benzylamine MS (ES+) m/e 3-yl)-1-ethyl-1H- 440[M + H]⁺ imidazo[4,5-c]pyridin- 7-yl]-N-benzyl-benzamide 1654-[2-(4-Amino-furazan- L-proline methyl MS (ES+) m/e 3-yl)-1-ethyl-1H-estser 462 [M + H]⁺ imidazo[4,5- c]pyridin-7- yl]-phenyl}- methanoyl)-pyrrolidine-2- carboxylic acid methyl ester 166 4-[2-(4-Amino- 1-methylMS (ES+) m/e furazan-3-yl)-1- piperazine 433 [M + H]⁺ethyl-1H-imidazo[4,5- c]pyridin-7- yl]-phenyl}-1-(4- methyl-piperazin-1-yl)-methanone

The following compounds were prepared by the general method described inExample 161 from the product of Example 160.

Example Amine Characterisation 167 3-[2-(4-Amino- phenethyl amine MS(ES+) m/e furazan-3-yl)-1- 454 [M + H]⁺ ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-N- phenethyl-benzamide 168 3-[2-(4-Amino- benzylamine MS(ES+) m/e furazan-3-yl)-1- 440 [M + H]⁺ ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-N- benzyl-benzamide 169 3-[2-(4-Amino- L-proline methylMS (ES+) m/e furazan-3-yl)-1- estser 462 [M + H]⁺ ethyl-1H-imidazo[4,5-c]pyridin-7- yl]-phenyl}- methanoyl)-pyrrolidine- 2-carboxylic acidmethyl ester 170 3-[2-(4-Amino- 1-methyl MS (ES+) m/e furazan-3-yl)-1-piperazine 433 [M + H]⁺ ethyl-1H-imidazo[4,5- c]pyridin-7-yl]-phenyl}-1-(4- methyl-piperazin-1-yl)- methanone 171 3-[2-(4-Amino-morpholine MS (ES+) m/e furazan-3-yl)-1- 420 [M + H]⁺ethyl-1H-imidazo[4,5- ]pyridin-7-yl]- phenyl}-1-morpholin-4-yl-methanone

EXAMPLE 172[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-phenyl-amine

Under Ar, a solution of the product from Example 100 (24 mg, 77.6 mol)in 1,4-dioxane (0.8 ml) and toluene (1.2 ml) was treated withTris(dibenzylidene-acetone)dipalladium (7.2 mg, 7.8 mol),racemic-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (9.7 mg, 15.6 mol),aniline (8.5 l, 93.1 mol), and sodium tert-butoxide (10.5 mg, 108.6mol). This mixture was then heated to 175° C. by microwave for 45 min.After cooled to ambient temperture, the reaction mixture was dilutedwith ethyl acetate (30 ml), filtered though a celite pad and then thefiltrate was concentrated in vacuo. The residue was purified withreverse phase HPLC (10% MeCN/H₂O→80% MeCN/H₂O), to afford the titlecompound, (6.3 mg, 24%); MS (ES+) m/e 322 [M+H]⁺.

The following examples were obtained by the method of Example 172.

Example Aniline Characterisation 173 [2-(4-Amino- 3-aminopyridineMS(ES+) m/e furazan-3-yl)-1- 323 [M + H]⁺ ethyl-1H-imidazo[4,5-c]pyridin-7- yl]-pyridin-3-yl-amine 174 [2-(4-Amino-furazan-3-4-morpholinoaniline MS (ES+) m/e yl)-1-ethyl-1H- 407 [M + H]+imidazo[4,5- c]pyridin-7- yl]-(4-morpholin- 4-yl-phenyl)-amine

EXAMPLE 1754-[1-Ethyl-7-(4-methoxy-phenylsulfanyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

Under Ar, a solution of the product from Example 100 (53.2 mg, 172 mol)in 1,4-dioxane (1 ml) and toluene (1.5 ml) was treated withTris(dibenzylidene-acetone)dipalladium (15 mg, 17 mol),racemic-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (20 mg, 34 mol),4-methoxybenzenethiol (26 l, 206 mol), and sodium tert-butoxide (23.5mg, 241 mol). This mixture was then heated to 175° C. by microwave for 1h. After cooled to ambient temperture, the reaction mixture was dilutedwith ethyl acetate (30 ml) and methanol (30 ml), filtered though acelite pad and then the filtrate was concentrated in vacuo. The residuewas purified with flash chromatography (hexanes/ethyl acetate 2:1), toafford the title compound, (35.6 mg, 56%); MS (ES+) m/e 369 [M+H]⁺.

The following example was obtained by the method of Example 175.

Example thiophenol Characterization 176 4-[1-Ethyl- benzenethiol MS(ES+)m/e 7-phenyl-sulfanyl)- 339 [M + H]⁺ 1H-imidazo[4,5- c]pyridin-2-yl]-furazan-3- ylamine

EXAMPLE 1774-(1-cyclopropyl-7-phenyl-1H-imidazo[4,5c]pyridin-2-yl)furazan-3-ylamine

Step 1. 3-Bromo-5-nitropyridin-4-ol

To a suspension of 4-hydroxy-3-nitropyridine (7.00 g, 50 mmol) in water(50 ml) was added bromine (3.23 ml, 63 mmol) dropwise at roomtemperature. The resulting mixture was stirred for one hour then heatedto 50° C. for two hours. After cooling to room temperature and stirringfor a further hour the product was filtered off, washed with water anddried under vacuum for two days, affording 9.54 g (87%); MS (AP−) m/e217/219 [M+H]⁺.

Step 2. 3-Bromo-4-chloro-5-nitro-pyridine

To phosphorous oxychloride (50 ml) cooled in ice was slowly added theproduct of step 1 (6.57 g, 30 mmol). To the resulting stirred solutionwas added N,N-diethylaniline (4.77 ml, 30 mmol) dropwise. The resultingmixture was warmed to room temperature, then heated to reflux for twohours. After this time the mixture was concentrated under vacuum and theresidue poured onto ice. The mixture was extracted into diethyl etherand the organic phase washed twice with water, followed by once withbrine before concentrating to a brown oil which solidified on standing,8.01 g (>100%); ¹H NMR (CDCl₃) 8.94 (1H, s), 8.93 (1H, s).

Step 3. (3-Bromo-5-nitro-pyridin-4-yl)-cyclopropyl-amine

To a solution of the product of Step 2 (8.01 g, ca. 30 mmol) indichloromethane (100 ml) at 0° C. was added cyclopropylamine (4.16 ml,60 mmol) drop-wise. The resulting mixture was stirred overnight at roomtemperature, then concentrated under vacuum to a residue andre-dissolved in ethyl acetate, basifying with sodium bicarbonate. Theorganic phase was washed with water three times, followed by twice withbrine before concentrating under vacuum to a crude solid. This oil waspurified by column chromatography eluting with a gradient of 50%DCM/hexane to DCM affording product as a yellow solid, 6.22 g (80%); MS(ES+) m/e 258/260 [M+H]⁺.

Step 4. 5-Bromo-N⁴-cyclopropyl-pyridine-3,4-diamine

To a stirred solution of the product obtained from Step 3 (2.95 g, 11.4mmol) in glacial acetic acid (50 ml) was added iron dust (3.35 g, 60mmol). The resulting mixture was stirred at 80° C. for 90 minutes, afterwhich it was filtered through Celite and the liquor concentrated undervacuum. The crude product was re-dissolved in ethyl acetate, basifiedwith sodium bicarbonate and refiltered. Th organic phase was washed withwater three times, followed by twice with brine before concentratingunder vacuum to give the product. Passed through a silica plug affordingproduct as an oil, 1.65 g (63%); MS (ES+) m/e 228/230 [M+H]⁺.

Step 5.4-(7-Bromo-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

The title compound was prepared from the product of Step 4 using themethod of Example 1 Steps 3 and 4; MS (ES+) m/e 321/323 [M+H]⁺.

Step 6.4-(1-Cyclopropyl-7-phenyl-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

The title compound was prepared from the product of Step 5 andphenylboronic acid using the method of Example 101; MS (ES+) m/e 319[M+H]⁺.

The following compounds were prepared from the product of Example 177,Step 5 and the corresponding boronic acid using the general method ofExample 101

178 4-[7-(4- 4-(Aminomethyl)- MS (ES+) m/e Aminomethylphenyl)-phenylboronic 348 [M + H]⁺. 1-cyclopropyl- acid 1H-imidazo[4,5-hydrochloride c]pyridin-2- yl]furazan-3-ylamine 179 4-(1-Cyclopropyl-7-2-Thiopheneboronic MS (ES+) m/e thiophen-2-yl-1 acid 325 [M + H]⁺.H-imidazo[4,5- c]pyridin-2-yl)furazan-3- ylamine

EXAMPLE 1804-(7-Bromo-1-phenyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

The title compound was prepared from the product of Example 177 Step 2and aniline using the method described in Example 177 Steps 3-5; MS(ES+) m/e 358 [M+H]⁺.

EXAMPLE 1814-(1-Phenyl-7-thiophen-2-yl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

A stirred mixture of the product from Example 180 (50 mg, 0.14 mmol),thiophene-2-boronic acid (27 mg, 0.21 mmol) and Pd(dppf)₂Cl₂.CH₂Cl₂ (11mg, 0.014 mmol) in 3.5 ml of 2.5:1 Dioxane/2 M K₂CO₃ contained in a 20ml pressure tube was heated to 110° C. for 18 h. The resulting biphasemixture was cooled to room temperature. The organic layer (top) wasremoved with pipet, filtered to remove the Pd. The aqueous layer wasextracted once with EtOAc. EtOAc was combined with the organic filtrate,washed with sat'd NaHCO₃, water, brine, dried (Na₂SO₄) and reduced invacuo. the residue was purified by silica gel chromatography elutingwith 10% MeOH in CHCl₃, to afford the title compound, (9 mg, 18%); MS(ES+) m/e 361 [M+H]⁺.

The following examples were prepared from the product of Example 180using the method described in Example 181.

Example Boronic acid Characterisation 182 4-(1,7-Diphenyl-1H-phenylboronic MS(ES+) m/e imidazo[4,5- acid 355 M + H]⁺ c]pyridin-2-yl)-furazan-3- ylamine 183 4-[2-(4-Amino- 4-hydroxybenzene MS (ES+) m/efurazan-3- boronic acid 371 [M + H]⁺ yl)-1-phenyl-1H- imidazo[4,5-c]pyridin- 7-yl]-phenol 184 4-[7-(3,5-Dimethyl 3,5-dimethyl MS(ES+) m/e isoxazole-4-yl)- isoxazole-4- 374 [M + H]⁺ 1-phenyl-1H-boronic acid imidazo[4,5- c]pyridin-2-yl]- furazan-3-ylamine

EXAMPLE 1854-[7-(4-Ethylaminomethyl-phenyl)-1-phenyl-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

Step 1.4-[2-(4-Amino-furazan-3-yl)-1-phenyl-1H-imidazo[4,5-c]pyridin-7-yl]-benzaldehyde

A stirred mixture the product of Example 180 (0.2 g, 0.56 mmol),4-formylbenzeneboronic acid (0.126 g, 0.84 mmol) and Pd(dppf)₂Cl₂.CH₂C)₂(0.046 g, 0.056 mmol) in 6.0 ml of 2.5:1 Dioxane/2 M K₂CO₃ contained ina 20 ml pressure tube was heated to 110° C. for 18 h. The resultingbiphase mixture was cooled to room temperature. The organic layer (top)was removed with pipet, filtered to remove the Pd. The aqueous layer wasextracted once with EtOAc. EtOAc was combined with the organic filtrate,washed with sat'd NaHCO₃, water, brine, dried (Na₂SO₄) and reduced invacuo. the residue was purified by silica gel chromatography elutingwith 10% MeOH in CHCl₃, to afford the title compound, (0.10 g, 47%); MS(ES+) m/e 383 [M+H]⁺.

Step 2.4-[7-(4-Ethylaminomethyl-phenyl)-1-phenyl-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

To a stirring solution of the product from step 1 (0.1 g, 0.26 mmol) andethylamine (in THF, 0.12 ml, 0.24 mmol) in methylene chloride (4 ml) wasadded sodium triacetoxyborohydride (0.055 g, 0.26 mmol) and acetic acid(0.4 ml). The reaction mixture was stirred overnight The solvent wasremoved and the residue was washed with sat'd NaHCO₃, extracted 3× withEtOAc water, dried (Na₂SO₄) and reduced in vacuo. The residue waspurified by silica gel chromatography eluting with 30% ethyl acetate inhexane, to afford the title compound, (0.016 g, 15%); MS (ES+) m/e 411[M+H]⁺.

EXAMPLE 1862-(4-Amino-furazan-3-yl)-1-phenyl-1H-imidazo[4,5-c]pyridine-7-carboxylicacid

A solution of the-product from Example 180 (0.1 g, 0.28 mmol) intetrahydrofuran (10 ml) at −78° C. was treated with 2 M solution lithiumdiisopropylamide (LDA, 0.28 ml, 0.56 mmol) in hexane under argon. After5 minutes the solution was treated with a 1.6 M solution of n-butyllithium (0.52 ml, 0.84 mmol) in hexane at −78° C. The mixture wasstirred for 10 mins, then carbon dioxide gas was bubbled through thesolution for 10 mins. The resulting pale yellow suspension was allowedto warm to room temperature over 2 h, water (1 ml) in tetrahydrofuran (3ml) was cautiously added dropwise and the mixture concentrated in vacuo.The residual solid was washed with ether (2×10 ml) then dissolved inmethanol (10 ml) containing glacial acetic acid. The solvent wasevaporated and the residue triturated under ether (2 ml) and filtered togive the title compound (10 mg, 11%); MS (ES+) m/e 323 [M+H]⁺.

EXAMPLE 1874-[7-Bromo-1-(4-methoxy-phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The title compound was prepared from the product of Example 177 Step 2and 4-methoxy-aniline using the method described in Example 177 Steps3-5; MS (ES+) m/e 388 [M+H]⁺.

EXAMPLE 1884-[2-(4-Amino-furazan-3-yl)-7-bromo-imidazo[4,5-c]pyridin-1-yl]-phenol

To a solution of the product from Example 187 (0.1 g, 0.26 mmol) inanhydrous dichloromethane (10 ml) stirred at 0° C., was added dropwiseboron tribromide (1.0 M solution in dichloromethane, 2.3 ml, 2.3 mmol)and the mixture stirred at room temperature for 16 hours. The reactionwas quenched with water (20 ml), basified to pH 14 with 50% sodiumhydroxide solution. The aqueous phase was washed with dichloromethane3×, neutralised with 6 N hydrochloric acid, and the resultingprecipitate collected, washed with water 3×, diethyl ether and dried invacuo to yield the title product (40 mg, 40%); MS (ES+) m/e 374 [M+H]⁺.

EXAMPLE 1894-{1-[4-(2-Dimethylamino-ethoxy)-phenyl]-7-phenyl-1H-Imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine

Step 1.4-{7-Bromo-1-[4-(2-dimethylamino-ethoxy)-phenyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine

The title compound was obtained from the product of Exaample 188 by themethod of Example 41; MS (ES+) m/e 444/446 [M+H]⁺.

Step 2.4-(1-[4-(2-Dimethylamino-ethoxy)-phenyl]-7-phenyl-1H-imidazo[4,5-c]pyridin-2-yl-furazan-3-ylamine

A stirred mixture of the product of Step 1 (0.1 g, 0.23 mmol),phenylboronic acid (41 mg, 0.34 mmol) and Pd(dppf)₂Cl₂.CH₂Cl₂ (19 mg,0.023 mmol) in 2.5 ml of 2.5:1 Dioxane/2 M K₂CO₃ contained in a 20 mlpressure tube was heated to 110° C. for 18 h. The resulting biphasemixture was cooled to room temperature. The organic layer (top) wasremoved with pipet, filtered to remove the Pd. The aqueous layer wasextracted once with EtOAc. EtOAc was combined with the organic filtrate,washed with sat'd NaHCO₃, water, brine, dried (Na₂SO₄) and reduced invacuo. the residue was purified by silica gel chromatography elutingwith 10% MeOH in CHCl₃, to afford the title compound, (16 mg, 16%); MS(ES+) m/e 442 [M+H]⁺.

The following examples were prepared from the product of Exaple 189,Step 1 using the method of Example 189, Step 2.

Example Boronic acid Characterisation 190 4-[1-[4-(2-Dimethylamino-4-fluorophenyl MS(ES+) m/e 460 ethoxy)-phenyl]-7-(4- boronic acid [M +H]⁺ fluoro-phenyl)-1H- imidazo[4,5-c]pyridin-2- yl]-furazan-3-ylamine

EXAMPLE 191[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-piperidin-4-yl-amine

Step 1.2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridine-7-carbaldehyde

A solution of the product from Example 100 (0.1 g, 0.324 mmol) intetrahydrofuran (4 ml) at −78° C. was treated with a 1.6M solution ofn-butyllithium (0.6 ml, 0.97 mmol) in hexanes. After 5 minutes themixture was treated with dimethylformamide (0.3 ml) and allowed to reachroom temperature. After 30 minutes at room temperature the reaction wascarefully quenched with water and extracted into dichloromethane (×2).The organic layer was then washed with brine, dried (Na₂SO₄) and reducedin vacuo. The residue was purified by silica gel chromatography elutingwith ethyl acetate, to afford the title compound, (0.034 g, 41%); MS(ES+) m/e 259 [M+H]⁺.

Step 2.4-{[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester

The title compound was prepared from the product of Step 1 and4-Amino-piperidine-1-carboxylic acid tert-butyl ester according to thegeneral method of Example 149; MS (ES+) m/e 443 [M+H]⁺.

Step 3.[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-piperidin-4-yl-amine

A solution of the product from Step 2 (0.075 g, 0.17 mmol) indichoromethane (1 ml) was treated with trifluoroacetic acid (1 ml).After 2 hours the reaction was reduced in vacuo, dissolved in methanoland applied to a SCX ion exchange column and eluted with methanol andthen a mixture of methanol/0.880 ammonia (9:1). The basic fractions werethen reduced to afford the title compound, (0.053 g, 91%); MS (ES+) m/e343 [M+H]⁺.

The following examples were prepared from the product of Example 191Step 1 using the method described in Example 149 followed by the methodof Example 191 Step 3

Example Amine Characterisation 192 1-[2-(4-Amino- Piperidin-4-yl-MS(ES+) m/e furazan-3- carbamic acid tert- 343 [M + H]⁺ yl)-1-ethyl-1H-butyl ester imidazo[4,5- c]pyridin-7- ylmethyl]- piperidin-4- ylamine193 4-(1-Ethyl-7- piperazine-1- MS (ES+) m/e piperazin-1- carboxylicacid tert- 329 [M + H]⁺ ylmethyl-1H- butyl ester imidazo[4,5-c]pyridin-2- yl)-furazan-3- ylamine

EXAMPLE 194N-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-N-piperidin-4-yl-acetamide

Step 1.4-{Acetyl-[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester

The title compound from Example 191, Step 2 (145 mg, 0.3 mmol) indichloromenthane at 0° C. was treated with potassium carbonate (90 mg,0.66 mmol) followed by acetyl chloride (26 mg, 0.33 mL), and the mixturewas stirred at room temperature for 1 hour. Purification of the residueby silica gel chromatography eluting with 10% methanol/dichloromethaneafforded the title compound (68 mg, 10%). MS (ES+) m/e 484 [M+H]⁺.

Step 2.N-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-N-piperidin-4-yl-acetamide

The title compound was prepared from the product of Step 1 and4-Amino-piperidine-1-carboxylic acid tert-butyl ester according to thegeneral method of Example 191 Step 3. MS (ES+) m/e 384 [M+H]⁺.

The following examples were prepared from the product of Example 191Step 1 using the method described in Example 149.

Example Amine Characterisation 195 4-{7-[(4-Bromo- 4-Bromo- MS(ES+) m/e429 benzylamino)-methyl]-1- benzylamine [M + H]⁺ ethyl-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3- ylamine 196 4-{1-Ethyl-7-[(3-methoxy-3-Methoxy- MS (ES+) m/e 380 benzylamino)-methyl]- benzylamine [M + H]⁺1H-imidazo[4,5-c]pyridin- 2-yl}-furazan-3-ylamine 1974-(1-Ethyl-7-morpholin-4- Morpholine MS(ES+) m/e 330ylmethyl-1H-imidazo[4,5- [M + H]⁺ c]pyridin-2-yl)furazan-3- ylamine 1984-(1-Ethyl-7-piperidin-1- Piperidine ¹H NMR(D⁶DMSO) δ 9.06ylmethyl-1H-imidazo[4,5- (1H, s), 8.27(1H, s), 6.96c]pyridin-2-yl)furazan-3- (2H, br s), 5.00(2H, q, J8, ylamine 13Hz),3.77(2H, s), 2.50− 2.25(4H, m), 1.56−1.30(9H, m) 199 4-[1-Ethyl-7-(4-1-Ethylpiperazine MS(ES+) m/e 357 ethylpiperazin-1-ylmethyl)-1H- [M +H]⁺ imidazo[4,5-c]pyridin-2- yl)furazan-3-ylamine

EXAMPLE 2004-{-Ethyl-7-[4-(4-fluoro-phenyl)-piperazin-1-ylmethyl]-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

The product of Example 191 Step 1 (0.10 g, 0.38 mmole) in1,2-dichloroethane (5 ml) was treated with 1-(4-fluorophenyl)piperazine(0.10 g, 0.58 mmole) and stirred at ambient temperature for 15 minutes.Sodium triacetoxyborohydride (0.16 g, 0.76 mmole) was added and thereaction mixture stirred at ambient temperature for 18 hours. Themixture was diluted with dichloromethane, washed (×2) with saturatedsodium hydrogen carbonate solution followed by saturated brine, driedover magnesium sulphate and concentrated in vacuo. The residue waspurified by column chromatography on silica gel eluting with ethylacetate to afford the title compound; MS (ES+) m/e 357 [M+H]⁺. Thefollowing examples were prepared from the product of Example 191 Step 1using the method described in Example 200.

Example Amine Characterisation 201 4-{1-Ethyl-7-[(3-1-(3-aminopropyl)pyrrolidine MS(ES+) m/e 371pyrrolidin-1-yl-propylamino)-methyl]- [M + H]⁺1H-imidazo[4,5-c]pyridin-2- yl}-furazan-3-ylamine 202[2-(4-Amino-furazan-3- 1-Methyl-4-(methylamino)- MS(ES+) m/e 371yl)-1-ethyl-1H-midazo[4,5- piperidine [M + H]⁺c]pyridin-7-ylmethyl]-methyl-(1- methyl-piperidin-4-yl)-amine 2034-[1-Ethyl-7-((S)-2- (S)-(+)-1-(2-pyrrolidinyl- MS(ES+) m/e 397pyrrolidin-1-ylmethyl- methyl)pyrrolidine [M + H]⁺pyrrolidin-1-ylmethyl)- 1H-imidazo[4,5-c] pyridin-2-yl]- furazan-3-ylamine 204 2-{4-[2-(4-Amino-furazan-3- 1-(Pyrrolidinocarbonyl- MS(ES+)m/e 440 yl)-1-ethyl-1H-imidazo[4,5- methyl)piperazine [M + H]⁺c]pyridin-7-ylmethyl]- piperazin-1-yl}-1-pyrrolidin- 1-yl-ethanone 2054-{1-Ethyl-7-[(2- 1-(2-Aminoethyl)-pyrrolidine MS(ES+) m/e 357pyrrolidin-1-yl-ethylamino)-methyl]- [M + H]⁺1H--imidazo[4,5-c]pyridin-2- yl}-furazan-3-ylamine 2064-[1-Ethyl-7-(4-methyl- N-Methyl-piperazine MS(ES+) m/e 343piperazin-1-ylmethyl)- [M + H]⁺ 1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3- ylamine 207 4-[1-Ethyl-7-((R)-2- (S)-(+)-1-(2-MS(ES+) m/e 397 pyrrolidin-1-ylmethyl- pyrrolidinylmethyl)pyrrolidine[M + H]⁺ pyrrolidin-1-ylmethyl)- (de Costa 1H-imidazo[4,5-c] et al, J.pyridin-2-yl]- furazan-3- Med. Chem., 1992; ylamine 35; 23, 4334-4343)208 4-[7-((S)-3-Dimethylamino- Dimethyl-(S)-pyrrolidin-3- MS(ES+) m/e357 pyrrolidin-1-ylmethyl)-1- yl-amine (Cesare, P. [M + H]⁺ethyl-1H-imidazo[4,5- et al, J. Med. Chem., 1992;c]pyridin-2-yl]-furazan-3- 35; 22, 4205-4213) ylamine 209[2-(4-Amino-furazan-3- 1-Methyl-piperidin-4-ylamine MS(ES+) m/e 357yl)-1-ethyl-1H-imidazo[4,5- (Brookes et al, J. Chem. [M + H]⁺c]pyridin-7-ylmethyl]- Soc., 1957; 3165-3171)(1-methyl-piperidin-4-yl)-amine 210 4-[1-Ethyl-7-((S)-2-4-(S)-1-Pyrrolidin-2-ylmethyl- MS(ES+) m/e 413 morpholin-4-ylmethyl-morpholine (Asami, M. et [M + H]⁺ pyrrolidin-1-ylmethyl)- al, Bull.Chem. Soc. Jpn, 1H-imidazo[4,5-c] 1990; 63, 3, 721-727)pyridin-2-yl]-furazan-3- ylamine 211 4-{1-Ethyl-7-[(3-3-Piperidin-1-yl-propylamine MS(ES+) m/e 385piperidin-1-yl-propylamino)- (Lehman, Chem. Ber., 1894; 27, [M + H]⁺methyl]-1H-imidazo[4,5-c] 2176) pyridin-2-yl}-furazan-3-ylamine 2124-{1-Ethyl-7-[(3- 3-Morpholin-4-yl-propylamine MS(ES+) m/e 387morpholin-4-yl-propylamino)- (Utermohlen et al, J. Amer. [M + H]⁺methyl]-1H-imidazo[4,5-c] Chem. Soc., 1941; 63,pyridin-2-yl}-furazan-3-ylamine 156-158) 213 4-(1-Ethyl-7-{[3-(4-3-(4-Methyl-piperazin-1-yl)- MS(ES+) m/e 400 methyl-piperazin-1-yl)-propylamine (Short, J. H., [M + H]⁺ propylamino]-methyl}- et al, J. Med.Chem., 1963; 1H-imidazo[4,5-c] 6, 275-283) pyridin-2-yl)-furazan-3-ylamine 214 4-[1-Ethyl-7-((S)-2-piperidin-1- 1-(S)-1-Pyrrolidin-2-MS(ES+) m/e 411 ylmethyl-pyrrolidin-1-ylmethyl)- ylmethyl-piperidine[M + H]⁺ 1H-imidazo[4,5-c] (Asami, M., Bull. pyridin-2-yl]-furazan-3-Chem. Soc. Jpn., ylamine 1990, 63(3), 721-7) 215 4-[7-((3R,5S)-3,5-cis-2,6- MS(ES+) m/e 357 Dimethylpiperazin-1-ylmethyl)-Dimethylpiperazine [M + H]⁺ 1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3- ylamine 216 4-[1-Ethyl-7-(4-4-(1-Pyrrolidinyl)piperidine MS(ES+) m/e 397 pyrrolidin-1-ylpiperidin-[M + H]⁺ 1-ylmethyl)-1H- imidazo[4,5-c]pyridin-2- yl)furazan-3-ylamine217 1-{4-[2-(4-Amino- 1-acetylpiperazine MS(ES+) m/e 371furazan-3-yl)-1-ethyl-1H-imidazo[4,5- [M + H]⁺c]pyridin-7-ylmethyl]-piperazin- 1-yl}-ethanone 2184-[7-((R)-3-Dimethylamino- Dimethyl-(R)-pyrrolidin-3-yl- MS(ES+) m/e 357pyrrolidin-1-ylmethyl)-1-ethyl- amine [M + H]+1H-imidazo[4,5-c]pyridin-2- yl]-furazan-3-ylamine 219[2-(4-Amino-furazan-3- 1-Isopropyl-4-amino- MS(ES+) m/e 385yl)-1-ethyl-1H-imidazo[4,5- piperidine [M + H]⁺c]pyridin-7-ylmethyl]-(1- isopropyl-piperidin-4-yl)-amine 220{(S)-1-[2-(4-Amino- (S)-1-Pyrrolidin-2- MS(ES+) m/e 344furazan-3-yl)-1-ethyl- yl-methanol [M + H]⁺ 1H-imidazo[4,5-c]pyridin-7-ylmethyl]- pyrrolidin-2-yl}-methanol 2213-{[2-(4-Amino-furazan- 3-Amino-propan-1-ol MS(ES+) m/e 3183-yl)-1-ethyl-1H-imidazo[4,5- [M + H]⁺ c]pyridin-7-ylmethyl]-amino}-propan-1-ol

The following examples were prepared from the product of Example 191Step 1 using the method described in Example 200 followed by the methoddescribed in Example 191 Step 3.

Example Amine Characterisation 222 4-[1-Ethyl-7-(pyrrolidin-3-Amino-pyrrolidine-1- MS(ES+) m/e 329 3-ylaminomethyl)-1H-imidazo[4,5-carboxylic acid tert- [M + H]⁺ c]pyridin-2-yl]-furazan-3-ylamine butylester (Falgueyret, J. P. et al, J. Med. Chem., 2001; 44, 1, 94-104) 2234-(1-Ethyl-7-{[((S)-1- (S)-2-Aminomethyl- MS(ES+) m/e 343pyrrolidin-2-ylmethyl)- pyrrolidine-1- [M + H]⁺ amino]-methyl}-1H-carboxylic acid tert- imidazo[4,5-c]pyridin-2- butyl ester (Slaitas,yl)-furazan-3-ylamine A. et al, Nucleosides Nucleotides, 2001; 20, 4-7,1377-1380) 224 4-(7-{[(4-Aminomethyl- (4-Aminomethyl- MS(ES+) m/e 385cyclohexylmethyl)- cyclohexylmethyl)- [M + H]⁺ amino]-methyl}-1-ethyl-carbamic acid tert- 1H-imidazo[4,5-c] butyl ester (Lum, R.pyridin-2-yl)-furazan-3- T., WO 9532945) ylamine 225 4-{1-Ethyl-7-[(2-4-(2-Amino-ethyl)- MS(ES+) m/e 372 piperazin-1-yl- piperazine-1- [M +H]⁺ ethylamino)-methyl]- carboxylic acid tert- 1H-imidazo[4,5-c] butylester pyridin-2-yl}-furazan-3- (Krapcho, A. et al, ylamine J. Med.Chem., 1998; 41, 27, 5429- 5444) 226 4-[7-((R)-3-Aminopyrrolidin-1-(3R)-(+)-(3-tert- MS(ES+) m/e 329 ylmethyl)-1-ethyl-1H-imidazo[4,5-butoxycarbonyl- [M + H]⁺ c]pyridin-2-yl)furazan-3-ylamineamino)pyrrolidine 227 4-[7-((S)-3-Aminopyrrolidin-1- (3S)-(−)-(3-tert-MS(ES+) m/e 329 ylmethyl)-1-ethyl-1H-imidazo[4,5-butoxycarbonylamino)pyrrolidine [M + H]⁺c]pyridin-2-yl)furazan-3-ylamine 228 4-(1-Ethyl-7-{[(pyrrolidin-2-2-(Aminomethyl)-1-N-tert- MS(ES+) m/e 343 ylmethyl)amino]methyl}-1H-butoxycarbonylpyrrolidine [M + H]⁺ imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine 229 [2-(4-Aminofurazan-3-yl)-1-ethyl-1H-1-tert-Butoxycarbonyl-4- MS(ES+) m/e 357 imidazo[4,5-c] ]pyridin-methylaminopiperidine [M + H]⁺ 7-ylmethyl]methylpiperidin-4- yl-amine230 {1-[2-(4-Aminofurazan- 4-[N-(tert-butoxycarbonyl)- MS(ES+) m/e 3573-yl)-1-ethyl-1H-imidazo[4,5- methylamino]piperidine [M + H]⁺ c]pyridin-7-ylmethyl]piperidin-4- (Russell et al, J. Med. Chem.yl}methylamine 1999; 42; 24, 4981-5001) 2314-(7-[1,4]Diazepan-1-ylmethyl- tert-butyl 1-homopiperazine MS(ES+) m/e343 1-ethyl-1H-imidazo[4,5-c]pyridin- carboxylate [M + H]⁺2-yl)-furazan-3-ylamine 232 4-(1-Ethyl-7-{[(piperidin-4-4-(aminomethyl)-1- MS(ES+) m/e 357 ylmethyl)-amino]-methyl}-1H-boc-piperidine [M + H]⁺ imidazo[4,5-c]pyridin-2- yl)furazan-3-yl amine233 N-[2-(4-aminofurazan- trans-(4-Amino- MS(ES+) m/e 3573-yl)-1-ethyl-1H- cyclohexyl)- [M + H]⁺ imidazo[4,5-c]pyridin-7-carbamic acid tert- methyl]-trans-cyclohexane-1,4- butyl ester(Bioorganic & diamine Medicinal Chemistry (2000), 8(6), 1451) 234{1-[2-(4-Amino-furazan- N-Methyl-piperidin- MS(ES+) m/e 3573-yl)-1-ethyl-1H- 4-yl-carbamic acid [M + H]⁺ imidazo[4,5-c] pyridin-tert-butyl ester 7-ylmethyl]-piperidin-4- yl}-methyl-amine 2354-{1-Ethyl-7-[(2-piperazin- 4-(2-Amino-ethyl)-piperazine-1- MS(ES+) m/e372 1-yl-ethylamino)-methyl]- carboxylic acid tert-butyl ester [M + H]⁺1H-imidazo[4,5-c]pyridin- (Krapcho et al, J. Med. Chem.,2-yl}-furazan-3-ylamine 1998; 41; 27, 5429-5444)

EXAMPLE 236{1-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-piperidin-4-yl}-cyclopropyl-amine

Step 1:4-[7-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-ylmethyl)-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The title compound was prepared from the product of Example 191, Step 1and 4-piperidone-ethylene-ketal using the method of Example 200. MS(ES+) m/e 386 [M+H]⁺.

Step2:1-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-piperidin-4-one

The product from Step 1 (0.245 g, 0.64 mmole) in 1,4-dioxane (20 ml) andaqueous hydrochloric acid (5M, 10 ml) was heated under reflux for 18hours. The mixture was allowed to cool to ambient temperature,neutralised by addition of aqueous sodium hydroxide solution (5M) andextracted into dichloromethane.

The combined organic extracts were dried under magnesium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluting with ethyl acetate to afford the title compound(0.054 g); MS (ES+) m/e 341 [M+H]⁺.

Step 3:{1-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-piperidin-4-yl}-cyclopropyl-amine

The title compound was prepared from the product of Step 2 andcyclopropylamine using the method of Example 200. MS (ES+) m/e 383[M+H]⁺.

EXAMPLE 237[2-(4-Amino-furazan-3-yl)-1-ethyl-1-H-imidazo[4,5-c]pyridin-7-ylmethyl]-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-aminedihydrochloride

The product of Example 191 Step 1 (150 mg, 0.58 mmole) in 5% acetic acidand dichloromethane (5 ml) was treated with8-Methyl-8-aza-bicyclo[3.2.1]oct-3-ylamine (179 mg, 1.2 mmole) andstirred at ambient temperature for 20 minutes. Sodium borohydride (13mg, 0.34 mmol) was added and the reaction mixture stirred at ambienttemperature for 20 hours. The product was diluted with dichloromethane,washed water followed by saturated brine, dried over sodium sulphate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluting with 20% ammonia in methanol/dichloromethane. toafford the title compound as a free base; (34 mg, 15%) MS (ES+) m/e 396[M+H]⁺. A solution of the resulting free base (34 mg, 0.08 mmol) inanhydrous methanol (1 ml) was treated with 1M hydrochloric acid in etherand stirred for 30 minutes. The resulting white precipitate was filteredand dried in vacuo to afford the title compound as a colourlesshydrochloride salt; (34 mg, 92%) MS (ES+) m/e 396 [M+H]⁺.

EXAMPLE 2384-{1-Ethyl-7-[(3-piperazin-1-yl-propylamino)-methyl]-1H-imidazo[4,5-c]pyridin-2-yl}-furazan-3-ylamine

Step 1: (3-Oxo-propyl)-carbamic acid tert-butyl ester

A solution of oxalyl chloride (0.27 ml, 3.15 mmole) in drydichloromethane (8 ml) was cooled to −78° C. Dimethyl sulfoxide (0.45ml, 6.29 mmole) in dichloromethane (1 ml) was added dropwise maintainingthe reaction temperature at −40° C. The reaction mixture was stirred for5 minutes and a solution of (3-hydroxy-propyl)-carbamic acid tert-butylester (0.50 g, 2.86 mmole) in dichloromethane (3 ml) was added dropwise.After stirring for 15 minutes, triethylamine (1.99 ml, 14.3 mmole) wasadded and the mixture allowed to warm to ambient temperature. Thereaction was quenched by adding water (10 ml), extracted withdichloromethane and the organic extracts were washed with aqueoushydrochloric acid solution (2M), saturated sodium bicarbonate solutionand water. The organic layer was dried under magnesium sulfate and thesolvent removed in vacuo to afford the title compound (0.45 g). ¹H NMR(CDCl3) δ 9.81 (1H, s), 3.45-3.40 (2H, t, J=5 Hz), 2.72-2.69 (2H, t, J=5Hz), 1.43 (9H, s).

Step 2: 4-(3-tert-Butoxycarbonylamino-propyl)-piperazine-1-carboxylicAcid 9H-fluoren-9-ylmethyl ester

Piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester hydrochloride(0.67 g, 1.93 mmole) was dissolved in methanol (5 ml), treated withdiisopropylamine (0.34 m], 1.93 mmole) and allowed to stir at roomtemperature for 5 minutes. The product from Step 1 (0.50 g, 2.89 mmole)and sodium cyanoborohydride (133 mg, 2.12 mmole) were added and themixture stirred under argon for 18 hours. The solvent was removed invacuo and the residue was dissolved in dichloromethane, washed withsaturated sodium bicarbonate solution, dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyeluting with ethyl acetate/hexane (1:1) to afford the title compound(0.71 g). ¹H NMR (CDCl3) δ 7.78-7.75 (2H, d), 7.59-7.56 (2H, d),7.41-7.31 (4H, m), 4.52-4.43 (2H, d), 4.27-4.20 (1H, t), 3.51-3.42 (4H,br m), 3.25-3.15 (2H, m), 2.45-2.35 (6H, m), 1.72-1.60 (2H, m), 1.45(9H, s).

Step 3: 4-(3-Amino-propyl)-piperazine-1-carboxylic Acid9H-fluoren-9-ylmethyl ester

The title compound was obtained from the product of step 2 by thegeneral method of Example 21. ¹H NMR (CDCl3) δ 7.78-7.75 (2H, d),7.60-7.55 (2H, d), 7.40-7.31 (4H, m), 4.48-4.44 (2H, d), 4.26-4.20 (1H,t), 3.50-3.41 (4H, br m), 3.01-2.94 (2H, m), 2.58-2.50 (2H, m),2.45-2.40 (4H, br m), 1.80-1.75 (2H, m).

Step 4:4-(3-([2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-amino}-propyl)-piperazine-1-carboxylicacid 9H-fluoren-9-ylmethyl Ester

The title compound was prepared from the product of Example 191 Step 1and the product from Step 3 using the method of Example 200. MS (ES+)m/e 608 [M+H]⁺.

Step 5: 4-{-Ethyl-7-[(3-piperazin-1yl-propylamino)-methyl]-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

The product from step 4 (0.17 g, 0.28 mmole) was dissolved indichloromethane (3 ml) and treated with piperidine (0.3 ml, 2.8 mmole).The mixture was stirred at room temperature under argon for 4 hours. Thesolvent was removed in vacuo and the residue purified by columnchromatography on silica gel eluting withammonia/methanol/dichloromethane (1:9:90) to afford the title compound(0.063 g). MS (ES+) m/e 386 [M+H]⁺.

EXAMPLE 2394-[1-Ethyl-7-((R)-2-morpholin-4-ylmethyl-pyrrolidin-1-ylmethyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

Step 1: (R)-2-Morpholin-4-ylmethyl-pyrrolidine-1-carboxylic acidtert-butyl ester

The title compound was prepared from N-(t-butoxycarbonyl)D-prolinal andmorpholine according to the general method of Example 200; MS (ES+), m/e271 [M+H]⁺.

Step 2: 4-(R)-1-Pyrrolidin-2-ylmethyl-morpholine

The title compound was prepared from the product of step 1 accoring tothe general method of Example 191 Step 3; MS (ES+), m/e 171 [M+H]⁺.

Step 3:4-[1-Ethyl-7-((R)-2-morpholin-4-ylmethyl-pyrrolidin-1-ylmethyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The title compound was prepared from the product of Step 2 and theproduct of Example 191 Step 1 using the procedures detailed in example200; MS (ES+), m/e 413 [M+H]⁺.

EXAMPLE 2404-[1-Ethyl-7-((R)-2-piperidin-1-ylmethyl-pyrrolidin-1-ylmethyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

Step 1: (R)-2-Piperidin-1-ylmethyl-pyrrolidine-1-carboxylic acidtert-butyl ester

The title compound was prepared from N-(t-butoxycarbonyl)D-prolinal andpiperidine using the procedure detailed in example 200; MS (ES+), m/e269 [M+H]⁺.

Step 2: 1-(R)-1-Pyrrolidin-2-ylmethyl-piperidine

The title compound was prepared from the product of step 1 using theprocedure detailed in Example 191 step 3; ¹H NMR (CDCl3) 3.24 (1H, m),2.96 (1H, m), 2.82 (1H, m), 2.45 (2H, m), 2.33-2.24 (4H, m), 1.95 (2H,br s), 1.85 (1H, m), 1.73 (2H, m), 1.57 (3H, m), 1.41 (2H, m), 1.31 (1H,m).

Step 3:4-[1-Ethyl-7-((R)-2-piperidin-1-ylmethyl-pyrrolidin-1-ylmethyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The title compound was prepared from the product of Step 2 and theproduct of Example 191 Step 1, using the general procedure of Example200; MS (ES+), m/e 411 [M+H]⁺.

EXAMPLE 2414-[1-Ethyl-7-((R)-2-piperazin-1-ylmethyl-cyclopentylmethyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

Step 1: 4-(R)-1-Pyrrolidin-2-ylmethyl-piperazine-1-carboxylic acid9H-fluoren-9-ylmethyl ester trifluoroacetate

To a solution of piperazine carboxylic acid 9-fluorenylmethyl esterhydrochloride (690 mg, 2 mmol), in dichloromethane was addeddiisopropylethylamine (258 mg, 2 mmol) followed byN(t-butoxycarbonyl)D-prolinal (400 mg, 2 mmol) and the resultingsolution was stirred for 10 minutes, and treated with sodiumtriacetoxyborohydride (850 mg, 4 mmol) and stirred for 4 hours at roomtemperature. The reaction was diluted with water and extracted withdichloromethane at pH 7. The combined organic phase was dried overanhydrous sodium sulfate. The dichloromethane solution was then treatedwith trifluoroacetic acid (5 ml) and stirred for 16 hours at roomtemperature. The solvent was evaporated in vacuo to afford the titlecompound; MS (ES+), m/e 392 [M+H]⁺.

Step 2:4-[1-Ethyl-7-((R)-2-piperazin-1-ylmethyl-cyclopentylmethyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The product of example 191 step 1 (100 mg, 0.387 mmol) was dissolved in1,2-dichloroethane (2.5 ml) and added to a stirred solution of theproduct of Step 1 (480 mg, 0.774 mmol) and diisopropyl ethylamine (100mg, 0.774 mmol) in 1,2-dichloroethane (2.5 ml). After stirring for 5minutes the reaction was treated with sodium triacetoxyborohydride (164mg, 0.774 mmol) and the reaction was stirred for 16 hours at roomtemperature. The reaction was then treated with piperidine (5 ml) andstirred for 5 hours at room temperature. The solvent was then evaporatedin vacuo and the residue diluted with dichloromethane, washed withsaturated sodium bicarbonate solution, water, brine, dried overanhydrous sodium sulfate and evaporated iv vacuo. The residue waspurified by automated reverse phase chromatography (Biotage flex,acetonitrile/water eluant) to afford the title compound (30 mg, 19%); MS(ES+), m/e 412 [M+H]⁺.

The following compounds were prepared by the general method of Example200 using ng materials indicated.

Aldehyde from Example Example # Amine Characterisation 2424-[1-Ethyl-7-(4-phenylaminomethyl- 191 Aniline MS(ES+) m/e 412phenyl)-1H-imidazo[4,5- [M + H]⁺ c]pyridin-2-yl]-furazan-3- ylamine 2434-[1-Ethyl-7-(4-fluoro-3- 113 Pyrrolidine MS (ES+) m/e 408pyrrolidin-1-ylmethyl- [M + H]⁺ phenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3- ylamine 244 4-[1-Ethyl-7-(3-fluoro-4- 119Pyrrolidine MS (ES+) m/e 408 pyrrolidin-1-ylmethyl- [M + H]⁺phenyl)-1H-imidazo[4,5- c]pyridin-2-yl]-furazan-3- ylamine 2454-[1-Ethyl-7-(4- 119 Ethylamine MS (ES+) m/e 382ethylaminomethyl-3-fluoro-phenyl)- [M + H]⁺ 1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

EXAMPLE 246(2-Furazan-3-yl-3-(2-methoxy-phenyl_-3-H-pyrolo(2,3-c)pyridin-4-ylmethyl)-piperidin-4-yl-amine

Step 1. (2-Bromo-6-nitro-pyridyl)-(2-methoxy-phenyl)-amine

The title compound was prepared from the product of Example 177, Step 2and 1-amino-2-methoxybenzene by the general method of Example 25 Step 1.MS (ES+) m/e 324 [M+H]⁺.

Step 2. 5-Bromo-N⁴-(2-methoxy-phenyl)-pyridine-3,4-diamine

A solution of the product of Step 1 (1 g, 3.08 mmol) in ethanol (11ml)/water (2.5 ml)/conc.HCl (1 ml) was stirred at 0° C. and iron filings(1 g, 18.5 mmol) were added protionwise. The mixture was warmed to roomtemperature and stirred for 18 hours. The mixture was poured onto icewater (100 ml) and basified using 1M sodium carbonate solution. Theresulting mixture was filtered through kieselgel and the pad was washedcopiously with ethanol. The organic phase was removed in vacuo to leavean orange emulsion, this was extracted into ethyl acetate, washed withwater (×3), dried using magnesium sulphate and evaporated in vacuo.Purification of the residue by silica gel chromatography eluting with 2%methanol in dicholomethane afforded the title compound (500 mg, 45%). MS(ES+) m/e 293 [M+H]⁺.

Step 3. 4-(7-bromo-1(2-methoxy-phenyl)-1H-imidazo(4,5-c)pyridin-2-yl)-furazan-3-ylamine

The title compound was obtained from the product of Step 2 by thegeneral method of Example 1 Steps 3 and 4; MS (ES+) m/e 387 [M+H]⁺.

Step 4.2-(4-Amino-furazan-3-yl)-1-(2-methoxy-phenyl)-1H-imidazo[4,5c)pyridine-7-carbaldehyde

The title compound was prepared from the product of Step 3 by thegeneral method of Example 191 Step 1; MS (ES+) m/e 337 [M+H]⁺.

Step 5.4-((2-(4-Amino-furazan-3-yl)-3-(2-methoxy-phenyl)-3H-pyrrolo(2,3-c)pyridin-4-ylmethyl)-amino)-piperidine-1-carboxylicacid tert butyl ester

The title compound was obtained from the product of Step and4-aminopiperidine-1-carboxylic acid tert butyl ester by the generalmethod of Example 200; MS (ES+) m/e 520 [M+H]⁺.

Step 6.(2-Furazan-3-yl-3-(2-methoxy-phenyl-3-H-pyrrolo(2,3-c)pyridin-4-ylmethyl)-piperidinyl-amine

The product of step 5 was treated according to the general method ofExample 191 Step 3.

A solution of the resulting free base (12 mg, 0.03 mmol) in anhydrousmethanol (0.5 ml) was treated with 1M hyrdrochloric acid in ether andstirred for 30 minutes. The resulting white precipitate was filtered anddried in vacuo to afford the title compound as a colourless solid (12mg, 63%); MS (ES+) m/e 420 [M+H]⁺.

EXAMPLE 247(3-Cyclopropyl-2-furazan-3-yl-3H-pyrrolo(2,3-c)pyridin-4-ylmethyl)-piperidin-4-yl-aminedihydrochloride

The title compound was prepared from the product of Example 177 Step 3using the methods of Example 246 Steps 2-6; MS (AP+) m/e 354 [M+H]⁺.

The following example was prepared by the general method described inExample 247.

Example Amine (C-7) Characterisation 248

piperazine-1-carboxylic acidtert-butyl ester MS(AP+) m/e 340[M+H]⁺4-(1-Cyclopropyl-7-piperazin-1- ylmethyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

EXAMPLE 249[2-(4-Amino-furazan-3-yl)-1-methyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-piperidin-4-yl-amine

Step 1: N-(2-Bromo-6-nitro-pyridyl)-methylamine

The title compound was prepared from 3-bromo-4-chloro-5-nitropyridineand methylamine by the general method of Example 246 Step 1. MS (ES+)m/e 329 [M+H]⁺.

Step 2:[2-(4-Amino-furazan-3-yl)-1-methyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-piperidin-4-yl-amine

The title compound was prepared from the product of Step 1 using themethods of Example 246 Steps 2-6; MS (ES+) m/e 328 [M+H]⁺.

EXAMPLE 2501-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-1-piperazin-1-yl-methanonedihydrochloride

Step 1.2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridine-7-carboxylicacid

A solution of the product from Example 100 (5 g, 18.25 mmol) intetrahydrofuran (200 ml) at −78° C. was treated with a 2M solutionlithium diisopropylamide (LDA, 18 ml, 36.5 mmol) in hexanes under argon.After 5 minutes the solution was treated with a 1.6M solution of n-butyllithium (34 ml, 54.7 mmol) in hexanes at −78° C. The mixture was stirredfor 10 mins, then carbon dioxide gas was bubbled through the solutionfor 10 mins. The resulting pale yellow suspension was allowed to warm toroom temperature over 2 h, water (10 ml) in tetrahydrofuran (30 ml) wascautiously added dropwise and the mixture concentrated in vacuo. Theresidual solid was washed with ether (2×100 ml) then dissolved inmethanol (100 ml) containing glacial acetic acid. The solvent wasevaporated and the residue triturated under ether (50 ml) and filteredto give the title compound as a buff coloured solid (3.28, 74%); MS(ES+) m/e 275 [M+H]⁺.

Step 2.4-{1-[2-(4-Amino-furazan-3-ul)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-methanoyl}-piperazine-1-carboxylicacid, tert-butyl ester.

1,1′-Carbonyldiimdazole (177 mg) was added to a solution of the productfrom Step 1 (0.1 g, 0.36 mmol) in dry DMF (5 ml) at room temperatureunder argon. The mixture was stirred for 18 h, thentert-butyl-1-piperazine carboxylate added. The mixture was stirred atroom temperature for 16 h, then partitioned between water (15 ml) andethyl acetate (3×15 ml). The combined organic extracts were washed withbrine (2×20 ml), dried over anhydrous sodium sulfate, filtered andevaporated. The residue was purified by silica gel chromatographyeluting with dichloromethane/ethanol/ammonia 300:8:1, to afford thetitle compound, (0.064 g, 40%); MS (ES+) m/e 443 [M+H]⁺.

Step 3.1-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-1-piperazin-1-yl-methanone,dihydrochloride

Ethereal hydrogen chloride (1.0M; 1 ml) was added to a solution of theproduct from Step 2 (0.064 g, 0.15 mmol) in methanol (1 ml) at roomtemperature under argon. The mixture was stirred for 16 h, the solventwas evaporated and the residue triturated under ether to give the titlecompound as a colourless solid (0.047, 79%); MS (ES+) m/e 343 [M+H]⁺.

EXAMPLE 251[2-(4-{1-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-methanoyl}-piperizin-1-yl)-ethyl]-carbamicacid tert-butyl ester

A mixture of the free base from Example 250, Step 3 (prepared by elutinga sample of the dihydrochloride salt through an SCX cartridge usingammonia (10%) in ethanol) and tert-butyl N-(2-oxoethyl)carbamate (0.065g, 0.41 mmol) in 1,2-dichloroethane (5 ml) was stirred at roomtemperature for 20 mins. This was then treated according to the methodof Example 200 to afford the title compound; MS (ES+) m/e 486 [M+H]⁺.

EXAMPLE 252[1-[4-(2-Amino-ethyl)-piperizin-1-yl)-1-[2-(4-amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-methanone.Dihydrochloride

Ethereal hydrogen chloride (1.0M; 1 ml) was added to a solution of theproduct from example 251 (0.042 g, 0.086 mmol) in methanol (2 ml) andthe solution stirred at room temperature for 16 h. The solvent wasevaporated and the residual solid triturated under ether (10 ml) andfiltered to give the title compound as a colourless solid (0.039 g,99%); MS (ES+) m/e 386 [M+H]⁺.

EXAMPLE 253 1-(4-[{-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-methanoyl}-piperazin-1-yl)-2-methylamino-ethanone

Step 1. [2-(4-{1-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-methanoyl}-piperazin-1]-yl)-2-oxo-ethyl]-methyl-carbamicacid tert-butyl ester

N-cyclohexylcarbodiimide, N-methyl polystyrene HL (1.69 mmol/g 515 mg,0.88 mmol) in dichloromethane (2 ml) was treated with Boc-Sarcosine (83mg, 0.44 mmol), followed by HOBT (59 mg, 0.44 mmol). The mixture wasstirred for 10 minutes, then treated with the title compound fromExample 250 (75 mg, 0.22 mmol) in triethylamine (92 ul, 0.66 mmol) anddichloromethane (1 ml). The reaction mixture was stirred for 2 hours,then passed down an SCX cartridge eluting methanol the 10% ammoniamethanol to afford the title compound (105 mg, 70%) MS (ES+) m/e 513[M+H]⁺.

Step 2.1-(4-[1-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo-[4,5-c]pyridin-7-yl]-methanoyl}-piperazin-1-yl)-2-methylamino-ethanone

The product of step 1 (105 mg, 0.2 mmol) was dissolved in DCM (2 ml) andhydrochloric acid in ether (1M, 10 equiv.) was added. The mixture wasstirred for 16 hours and the resulting white precipitate was filteredand dried in vacuo to afford the title compound as a colourless solid(44 mg, 52%); MS (ES+) m/e 413 [M+H]⁺.

The following examples were prepared from the product of Example 250.Using the two-step method described in Example 253 Steps 1 and 2.

Example Acid Characterisation 254

Boc-Glycine MS(ES+) m/e 399[M+H]⁺ 255

Boc-Beta-L-alanine MS(ES+) m/e 413[M+H]⁺ 256

Boc-L-alanine MS(ES+) m/e 413[M+H]⁺ 257

Boc-D-alanine MS(ES+) m/e 413[M+H]⁺ 258

Boc-L-proline MS(ES+) m/e 439[M+H]⁺

The following examples were prepared from the product of Example 250Step 1 using the two-step method described in example 250 Steps 2 and 3

Example Amine Characterisation 259 2-(4-Amino-furazan-3-yl)-1-4-Aminomethyl MS(ES+) m/e 371 ethyl-1H-imidazo[4,5-piperidin-1-carboxylic [M + H]⁺ c]pyridine-7-carboxylic acid acidtert-butyl ester (piperidin-4-yl methyl)-amide dihydrochloride 260 (+/−)2-(4-Amino-furazan-3-yl)- (+/−)-3-Amino MS(ES+) m/e 3571-ethyl-1H-imidazo[4,5- piperidine-1- [M + H]⁺ c]pyridine-7-carboxylicacid carboxylic acid tert- (piperidin-3-ylamide butyl esterdihydrochloride 261 2-(4-Amino-furazan-3-yl)-1- 4-Amino-piperidine-1-MS(ES+) m/e 357 ethyl-1H-imidazo[4,5- carboxylic acid tert- [M + H]⁺c]pyridine-7-carboxylic acid butyl ester piperidin-4-ylamidedihydrochloride 262 2-(4-Amino-furazan-3-yl)-1- (3-Amino-propyl)-MS(ES+) m/e 345 ethyl-1H-imidazo[4,5- methyl-carbamic acid [M + H]⁺c]pyridine-7-carboxylic acid (3- tert-butyl estermethylamino-propyl)-amide dihydrochloride 2632-(4-Amino-furazan-3-yl)-1- (4-Amino-butyl)- MS(ES+) m/e 345ethyl-1H-imidazo[4,5- carbamic acid tert [M + H]⁺c]pyridine-7-carboxylic acid (4- butyl ester amino-butyl)-amidedihydrochloride 264 2-(4-Amino-furazan-3-yl)-1- (6-Amino-hexyl)- MS(ES+)m/e 373 ethyl-1H-imidazo[4,5- carbamic acid tert [M + H]⁺c]pyridine-7-carboxylic acid (6- butyl ester amino-hexyl)-amidedihydrochloride 265 (+/−)-2-(4-Amino-furazan-3-yl)- 2-Aminomethyl-MS(ES+) m/e 471 1-ethyl-1H-imidazo[4,5- piperidine-1- [M + H]⁺c]pyridine-7-carboxylic acid carboxylic acid tert- (piperidin-2-ylmethyl)-amide butyl ester dihydrochloride 2661-[2-(4-Amino-furazan-3-yl)-1- (R)-Pyrrolidin-3-yl- MS(ES+) m/e 343ethyl-1H-imidazo[4,5- carbamic acid tert- [M + H]*c]pyridine-7-yl]-1-((R)-3-amino- butyl ester [alpha]D(27.6)C = -3.34pyrrolidin-1-yl)-methanone (c = 2.75%, DMF) dihydrochloride 2671-[2-(4-Amino-furazan-3-yl)-1- (S)-Pyrrolidin-3-yl- MS(ES+) m/e 343ethyl-1H-imidazo[4,5- carbamic acid tert- [M + H]⁺c]pyridine-7-yl]-1-((S)-3-amino- butyl ester [alpha]D(27.2)C = +1.31pyrrolidin-1-yl)-methanone (c = 3.75%, DMF) dihydrochloride 2682-(4-Amino-furazan-3-yl)-1- (R)-3-Amino- MS(ES+) m/e 343ethyl-1H-imidazo[4,5- pyrrolidine-1- [M + H]⁺ c]pyridine-7-carboxylicacid carboxylic acid tert- (R)-pyrrolidin-3-ylamide butyl esterdihydrochloride 269 2-(4-Amino-furazan-3-yl)-1- (S)-3-Amino- MS(ES+) m/e343 ethyl-1H-imidazo[4,5- pyrrolidine-1- [M + H]⁺c]pyridine-7-carboxylic acid carboxylic acid tert-(S)-pyrrolidin-3-ylamide butyl ester dihydrochloride 2702-(4-Amino-furazan-3-yl)-1- 2-Aminomethyl- MS(ES+) m/e 373ethyl-1H-imidazo[4,5- morpholine-4- [M + H]⁺ c]pyridine-7-carboxylicacid carboxylic acid tert- (morpholin-2-ylmethyl)-amide butyl esterdihydrochloride

EXAMPLE 2712-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridine-7-carboxylicacid[1-(2-amino-ethanoyl)-piperidine-4-yl]-amide dihyrochloride

Step 1.{2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridine-7-yl]-methanoyl}-amino)-piperidin-1-yl]-2-oxo-ethyl}-carbamicacid tert-butyl ester

A mixture of N-cyclohexylcarbodiimide, N-methyl polystyrene HL (1.69mmol/g; 300 mg, 0.507 mmol) and tert-butoxycarbonylamino-acetic acid (82mg, 0.466 mmol) in dry dichloromethane (3 ml) was stirred for 10 mins atroom temperature under argon. 1-hydroxybenzotriazole hydrate (HOBT; 71mg 0.466 mmol) was added and the mixture stirred for a further 10 mins.A solution of the product from example 261 (0.1 g, 0.233 mmol) andtriethylamine (0.1 ml, 0.507 mmol) in dry DMF (3 ml) was added and themixture stirred for 16 h. The mixture was then applied to a SCX ionexchange column, eluted with methanol and then a mixture ofmethanol/0.880 ammonia (9:1). The basic fractions were then evaporatedand the residual solid triturated under ether and filtered to afford thetitle compound, (0.067 g, 56%); MS (ES+) m/e 514 [M+H]⁺.

Step 2 .2-(4-Amino-furazan-3-yl)-1-ethyl-11H-imidazo[4,5-c]pyridine-7-carboxylicacid[1-(2-amino-ethanoyl)-piperidine-4-yl]-amide dihyrochloride

Ethereal hydrogen chloride (1.0M; 2 ml) was added to a solution of theproduct from Step 1 (0.067 g, 0.13 mmol) in methanol (3 ml) at roomtemperature under argon. The mixture was stirred for 16 h, the solventwas evaporated and the residue triturated under ether to give the titlecompound as a colourless solid (0.058, 79%); MS (ES+) m/e 414 [M+H]⁺.

The following examples were prepared from the product of Example 261using the two-step method described in Example 271 Step 1

Example Acid Characterisation 272 2-(4-Amino-furazan-3-yl)- 3-Amino-MS(ES+) m/e 428 1-ethyl-1H-imidazo[4,5- propionic acid [M + H]⁺c]pyridine-7-carboxylic acid [1-(3-amino- propanoyl)-piperidin-4-yl]-amide dihydrochloride 273 2-(4-Amino-furazan-3-yl)- (S)-Pyrrolidine-MS(ES+) m/e 454 1-ethyl-1H-imidazo[4,5- 2-carboxylic acid [M + H]⁺c]pyridine-7-carboxylic acid [1-((s)-1-pyrrolidin-2-yl-methanoyl)-piperidin- 4-yl]-amide dihydrochloride

The following examples were prepared from the product of Example 250Step 1 using the method described in example 250 Step 2

Example Amine Characterisation 274 1-[2-(4-Amino-furazan-3- pyrrolidineMS(ES+) m/e 328 yl)-1-ethyl-1H- [M + H]⁺ imidazo[4,5-c]pyridin-7-yl]-1-pyrrolidin-1-yl- methanone

EXAMPLE 2751-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-1-(S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanonedihydrochloride

Step 11-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-1-imidazol-1-yl-methanone

1,1′-Carbonyldiimdazole (0.89 g) was added to a solution of the productfrom Example 250 Step 1 (0.5 g, 1.82 mmol) in dry DMF (10 ml) at roomtemperature under argon. The mixture was stirred for 18 h resulting inthe precipitation of a colourless solid. Ether (10 ml) was added and thesolid filtered to give the title compound, (0.5 g, 85%); MS (ES+) m/e325 [M+H]⁺.

Step 21-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]-1-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone

A mixture of (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (0.142 g; 0.93mmol) and the product from Step 1 (0.1 g; 0.31 mmol) in DMF (2 ml) waswarmed at 60° C. for 18 h. The cooled mixture was partitioned betweenwater (10 ml) and ethyl acetate (3×10 ml). The combined organic extractswere washed with brine (2×20 ml), dried over anhydrous sodium sulphate,filtered and evaporated to give a colourless gum. The crude material waspurified by preparative HPLC using Dynamax C18 column, 8 micron particlesize; 250 mm×41.4 mm i.d.; 10-90% acetonitrile/water (0.1% TFA); 70ml/min; UV detection at 254 nm) to afford the title compound, (0.055 g,28%); MS (ES+) m/e 411 [M+H]⁺.

EXAMPLE 2762-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridine-7-carboxylicacid (R)-pyrrolidin-3-yl amide

The product of Example 275 Step 1 (150 mg) and(R>3-amino-1-pyrrolidine-1-carboxylic acid tert-butyl ester (172 mg)were reacted according to the general method of Example 275, Step 2followed by the general method described in example 250 step 3 to givethe title compound; MS (ES+) m/e 443 [M+H]⁺.

The following example was prepared by the general method described inExample 276

Example Amine Characterisation 277 2-(4-Amino-furazan- (R)-3-amino-1- MS(ES+) m/e 3-yl)-1-ethyl- pyrrolidine-1- 367 [M + H]⁺ 1H-imidazo[4,5-carboxylic acid c]pyridine-7- tert-butyl ester carboxylic acid(R)-pyrrolidin-3-yl amide

EXAMPLE 2782-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazol-4,5-c]pyridine-7-carboxylicacid (2-piperizin-1-yl-ethyl)-amide dihydrochloride

Step 1.4-[2-({1-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridine-7-yl]-methanoyl}-amino)-ethyl]-piperizin-1-carboxylicacid benzyl ester

The product of Example 250 Step 1 and4-(2-amino-ethyl)-piperizine-1-carboxylic acid benzyl ester were reactedaccording to the general method of Example 250, Step 2 to give the titlecompound; MS (ES+) m/e 520 [M+H]⁺.

Step2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridine-7-carboxylicacid (2-piperizin-1-yl-ethyl)-amide dihydrochloride

Hydrogen bromide (30% in acetic acid; 0.5 ml) was added to a solution ofthe product from Step 1 (0.085 g, 0.165 mmol) in dry dichloromethane (5ml) at room temperature under argon. The mixture was stirred for 10mins. resulting in the precipitation of a colourless solid which wasfiltered off, partitioned between sodium carbonate solution (2N, 5 ml)and ethyl acetate (2×10 ml). The combined organic extracts were dried(Na2SO4), evaporated, dissolved in methanol (2 ml) and ethereal HCl(1.0M; 0.5 ml) added. The solvent was then evaporated and the residuetriturated with ether (2 ml) and filtered to give the title compound (16mg, 21%); MS (ES+) m/e 386 [M+H]⁺.

EXAMPLE 279[4-(7-Bromo-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-yl]-carbamicacid tert-butyl ester

A solution of the product from Example 100 (1.0 g, 3.23 mmol) indichloroethane (5 mL) and pyridine (10 mL) was treated with DMAP (0.435g, 3.56 mmol) and BoC₂O (1.06 g, 4.85 mmol). The solution was heated to70° C. and was stirred overnight. The reaction is not complete, so moreDMAP (0.197 g, 1.62 mmol) and Boc₂O (0.353 g, 1.62 mmol) were added, andthe reaction mixture was stirred overnight. The reaction mixture wasthen cooled, and concentrated in-vacuo. The black residue was dissolvedup in H₂O and EtOAc, and the product was extracted into the organiclayer. The layers were separated, and the organic layer was dried overNa₂SO₄, filtered, and concentrated to give the pure product as a tansolid (1.25 g, 95%); MS (ES+) m/e 410 [M+H]⁺.

EXAMPLE 2804-[7-((S)-3-Amino-pyrrolidine-1-sulfonyl)-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

Step 1.{4-[7-((S)-3-tert-Butoxycarbonylamino-pyrrolidine-1-sulfonyl)-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-yl)-carbamicacid tert-butyl ester A solution of the product from Example 279 (0.150g, 0.367 mmol) in tetrahydrofuran (2 ml) at ambient temperature wastreated with NaH (60%) under Argon. After 10 minutes, the mixture wascooled to −78° C., and was treated with n-butyllithium. After 10minutes, the mixture was treated with a SO₂ solution (2 mL), formed frombubbling SO₂ gas into THF (2 mL). After 10 minutes of stirring, themixture was treated with SO₂Cl₂, and was allowed to warm to ambienttemperature. The reaction mixture was then concentrtated, in-vacuo, todryness. The solid was dissolved in dichloromethane (2.5 mL) andpyridine (2.5 mL) under Argon, and was treated with the amine (0.085 g,0.46 mmol), and was stirred at ambient temperature overnight. Thecompleted reaction was concentrated down to afford the title compound;MS (ES+) m/e 580 [M+H]⁺.Step 2.4-[7-((S)-3-Amino-pyrrolidine-1-sulfonyl)-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The title compound was prepared by dissolving the product, from Step 1,in a minimal amount of MeOH, and adding 1 mL of a 1M solution of HCl inEt₂O. The mixture was stirred for 6 hours, then concentrated in-vacuo todryness, taken up in DMSO, and purified via reverse-phase HPLC to givethe title compound (0.0443 g, 32%); MS (ES+) m/e 379 [M+H]⁺.

The following examples were prepared from the product of Example 279using the method described in Example 280.

Example Amine Characterisation 281 2-(4-Amino-furazan-3-yl)- MethylamineMS (ES+) m/e 324 1-ethyl-1H-imidazo[4,5- [M + H]⁺ c]pyridine-7-sulfonicacid methylamide 282 2-(4-Amino-furazan-3-yl)- Dimethylamine MS (ES+)m/e 338 1-ethyl-1H-imidazo[4,5- [M + H]⁺ c]pyridine-7-sulfonic aciddimethylamide

EXAMPLE 2832-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-ol

A solution of the product from Example 100 (2.6 g, 8.41 mmol) intetrahydrofuran (180 ml) at −78° C. was treated with a 2.5M solution ofn-butyllithium (8.41 ml, 21.03 mmol) in hexanes. After the addition wascomplete the mixture was treated with trimethylborate (2.62 g, 25.23mmol) and allowed to reach room temperature. After 1.5 hours at roomtemperature the reaction was carefully quenched with 3M aq. NaOH (12.5ml) followed by a 30% aqueous hydrogen peroxide solution (4.3 ml). After45 minutes the reaction was acidified with 2M hydrochloric acid and thenapplied to a SCX ion exchange column and eluted with methanol and then amixture of methanol/0.880 ammonia (9:1). The basic fractions were thenreduced and the solid residue was triturated with dichloromethane andfiltered to afford the title compound, (1.2 g, 58%); MS (ES+) m/e 247[M+H]⁺.

EXAMPLE 2844-[1-Ethyl-7-(piperidin-4-ylmethoxy)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

Step 1.4-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester

A mixture of the product from Example 283 (0.1 g, 0.406 mmol) and K₂CO₃(0.112 g, 0.812 mmol) in acetone (3 ml) at −78° C. was treated with4-iodomethylpiperidine-1-carboxylic acid tert-butyl ester (Villalobos,A; et al, J. Med. Chem., 1994, 37(17), 2721) (0.145 g, 0.447 mmol) andheated at reflux for 18 hours. A further portion of4-iodomethylpiperidine-1-carboxylic acid tert-butyl ester (0.145 g,0.447 mmol) was then added and the heating continued for a further 6hours. The reaction was then cooled, poured into water, extracted withdichloromethane, dried with NaSO₄ and reduced. The residue waschromatographed on silica gel eluting with ethyl acetate to afford thetitle compound, (0.071 g, 39%); MS (ES+) m/e 444 [M+H]⁺.

Step 2.4-[1-Ethyl-7-(piperidin-4-ylmethoxy)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The product from Step 1 (0.071 g, 0.16 mmol) was stirred intrifluoroacetic acid (0.5 ml) and dichloromethane (1 ml) at roomtemperature for 1 hour and the solution was then co-evaporated threetimes with dichloromethane. The residue was purified by silica gelchromatography eluting with 0.880 ammonia:methanol:dichloromethane(1:9:90), to afford the title compound, (0.046 g, 83%); MS (ES+) m/e 334[M+H]⁺.

EXAMPLE 2854-[1-Ethyl-7-(piperidin-4-yloxy)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

Step 1:4-[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yloxy]-piperidine-1-carboxylicacid tert-butyl ester

A mixture of the product from Example 283 (0.1 g, 0.406 mmol),4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.074 g, 0.369mmol) and tributylphosphine (0.074 g, 0.369 mmol) in tetrahydrofuran (5ml) was treated with 1,1′-(Azodicarbonyl)-dipiperidine (0.093 g, 0.369mmol) and heated at reflux for 18 hours. The reaction was then cooled toRT and then applied to a SCX ion exchange column and eluted withmethanol and then a mixture of methanol/0.880 ammonia (9:1). The basicfractions were then reduced and the solid residue chromatographed onsilica gel eluting with ethyl acetate to afford the title compound,(0.03 g, 17%); MS (ES+) m/e 430 [M+H]⁺.

Step 2:4-[1-Ethyl-7-(piperidin-4-yloxy)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The product from Step 1 (0.03 g, 0.07 mmol) was treated according to themethod of Example 284 Step 2 to afford the title compound, (0.02 g,87%); MS (ES+) m/e 330 [M+H]⁺.

EXAMPLE 2864-{1-ethyl-7-[(E)-2-(4-methoxyphenyl)-vinyl]-1H-imidazo[4,5-c]pyridin-2-yl}furazan-3-ylamine

The product of example 100 (309 mg, 1 mmol), 4-methoxystyrene (167 uL,1.25 mmol), palladium(II) acetate (12 mg, 0.05 mmol),o-tolyltriphenylphosphine (30 mg, 0.10 mmol) and triethylamine (349 uL,2.5 mmol) were heated at 130° C. for 4 hours. The solution waspartitioned between ethyl acetate and water, extracting withethylacetate (×3). Combined extracts were washed with water (×3), brine,dried over anhydrous magnesium sulfate and concentrated to a crudesolid, 450 mg, then purified by column chromatography eluting with1:9:90.880 ammonia:ethanol:dichloromethane affording the title product,176 mg (49%); MS (ES+) m/e 363 [M+H]⁺.

EXAMPLE 2874-[1-Ethyl-7-(2-piperidin-4-yl-ethyl)1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

A solution of 4-vinyl-piperidine-1-carboxylic acid tert-butyl ester (WO9620192) (1.2 mM: 252 mg) in dry tetrahydrofuran (4 ml) was treated witha 0.5M solution of 9-borabicyclo[3.3.1]-nonane in tetrahydrofuran (1.2mM; 2.4 ml) and stirred at room temperature for 6 hours under argon. Themixture was treated with the product of Example 100 (1.0 mM; 309 mg),1,1′-bis(diphenylphosphino)ferrocene dichloro palladium(II) complex withdichloromethane (25 mg) and a 3M aqueous solution of sodium hydroxide (1ml). The resulting mixture was heated at reflux under argon for 18 hoursand purified on a 5 g SCX ion exchange cartridge. After removal of thesolvent in vacuo the resulting yellow gum was treated withtrifluoroacetic acid at room temperature for 2 hours and the solutionpassed through a 5 g SCX ion exchange cartridge. The solvent was removedin vacuo and the residue purified on a 5 g silica solid phase extractioncartridge eluting with 1-5-94 ammonia-methanol-dichloromethane to givethe title compound as a white solid (23 mg). MS (ES+) m/e 342 [M+H]⁺.

EXAMPLE 2884-(1-Ethyl-5-oxy-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

A solution of the product of Example 1 (200 mg, 0.869 mmol) in aceticacid (2 ml) was treated with hydrogen peroxide (30%, 0.108 mg, 0.957mmol) and the mixture heated 90° C. for 5 hours. After cooling to roomtemperature the mixture was poured into sodium carbonate solution andextracted with dichloromethane (×4). The organic phase was dried, thesolvent was evaporated in vacuo and the residue purified by silica gelchromatography eluting with 15% methanol in dichloromethane, to affordthe title compound (130 mg, 53%); MS (ES+) m/e 247 [M+H]⁺.

EXAMPLE 2894-(4-Chloro-1-ethyl-1H-imidazol-[4,5-c]pyridin-2-yl)furazan-3-ylamine

A solution of the product of Example 288 (80 mg, 0.325 mmol) inphosphorus oxychloride (4 ml) was heated at 120° C. for 6 hours. Aftercooling to room temperature the mixture was concentrated in vacuo andthe residue partitioned between dichloromethane and saturated sodiumhydrogen carbonate solution. The organic phase was dried and the solventwas evaporated in vacuo to afford the title compound (81 mg, 100%) whichwas used directly in the next reaction; MS (ES+) m/e 265/267 [M+H]⁺.

EXAMPLE 2904-(1-Ethyl-4-phenyl-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

The title compound was prepared from the product of Example 289 andphenylboronic acid by the general method described in Example 49. MS(ES+) m/e 307 (M+H]⁺.

EXAMPLE 2914-(1-Ethyl-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

A solution of the product of Example 289 (0.1 g, 0.377 mmol) in1,4-dioxan (8 ml) was treated with a 2M solution of trimethylaluminium(0.378 ml, 0.755 mmol) in toluene andbis(triphenylphosphine)palladium(II) dichloride (0.026 g, 0.0377 mmol).The mixture was heated at reflux for 4 hours and then cooled to roomtemperature, quenched carefully with water, poured into dichloromethaneand washed with saturated sodium bicarbonate solution. The organic layerwas then dried, reduced and the residue chromatographed on silica geleluting with a mixture of dichloromethane and methanol (9.5/0.5) toafford the title compound, (0.022 g, 13%); MS (ES+) m/e 245 [M+H]⁺.

EXAMPLE 2924-(7-Bromo-1-ethyl-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

The title compound was prepared from 2-methyl-3-nitro-pyridin-4-ol (J.Med. Chem. 1989, 32, 2474-2485), using the procedures detailed inexample 100 step 1, and example 36 steps 1, 2 and 3; MS (ES+), m/e323/325 [M+H]⁺.

EXAMPLE 293[2-(4-Amino-furazan-3-yl)-7-bromo-1-ethyl-1H-imidazo[4,5-c]pyridin-4-yl]-methanol

Step 1:4-(7-Bromo-1-ethyl-4-methyl-5-oxy-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

The title compound was prepared from the product of Example 292 usingthe procedure detailed in example 155; MS (ES+), m/e 339/341 [M+H]⁺.

Step 2: Acetic Acid2-(4-amino-furazan-3-yl)-7-bromo-1-ethyl-1H-imidazo[4,5-c]pyridin-4-ylmethylester

The product of step 1 (565 mg, 1.66 mmol) was added to preheated aceticanhydride (5 ml, 53 mmol) at 110° C. and stirred for 1 hour. Thereaction was then cooled to RT and applied to a Mega Bond Elute SCX ionexchange column and eluted with methanol and then a mixture ofmethanol/0.880 ammonia (9:1). The basic fractions were reduced and thesolid residue chromatographed on silica gel eluting with a mixture ofdichloromethane/diethyl ether (9:1) to afford the title compound (300mg, 43%); MS (ES+), m/e 423/425 [M+H]⁺.

Step 3:[2-(4-Amino-furazan-3-yl)-7-bromo-1-ethyl-1H-Imidazo[4,5-c]pyridin-4-yl]-methanol

To a suspension of the product of step 2 (312 mg, 0.74 mmol) in methanol(10 ml) was added a 2M aqueous solution of sodium hydroxide (1.1 ml,2.21 mmol) and the reaction heated at reflux for 1 hour. The reactionwas then diluted with water (20 ml) and aged at room temperature for 2hours. The resulting precipitate was collected, washed with water anddried in vacuo at 45° C. for 16 hours to afford the title compound (220mg, 88%); MS (ES+), m/e 339/341 [M+H]⁺.

EXAMPLE 2944-(1-Ethyl-4-pyrazol-1-yl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

To a solution of pyrazole (472 mg, 6.96 mmol) in dimethylformamide (4ml) at 0° C. was added portionwise sodium hydride (60% dispersion inmineral oil, 167 mg, 6.96 mmol). The reaction was then treated with asolution of the product of example 289 (200 mg, 0.87 mmol) indimethylformamide (2 ml) and heated at 60° C. for 3 days. The reactionwas cooled and diluted with ethyl acetate (25 ml), then washedsequentially with saturated sodium bicarbonate solution, water, brine,dried over anhydrous sodium sulfate and evaporated in vacuo. The residuewas purified using silica gel chromatography eluting with a mixture of0.880 ammonia:methanol:dichloromethane (5:95) to afford the titleproduct (30 mg, 12%). MS (ES+) m/e 297 [M+H]⁺.

EXAMPLE 2954-(1-Cyclopropyl-6-methoxy-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

Step 1. 4-Methoxy-5-nitro-1H-pyridin-2-one

To a stirred solution of potassium tert-butoxide (2.8 g, 25 mmol) inliquid ammonia (30 ml) at −30° C. was added dropwise a solution of4-methoxy-3-nitropyridine (1.54 g, 10 mmol), tert-butyl hydroperoxide(5M in decane, 2.2 ml, 11 mmol) in tetrahydrofuran (10 ml) over 20minutes. After stirring at −30° C. for 30 minutes saturated ammoniumchloride solution (ca 5 ml) was cautiously added and the mixture allowedto warm to room temperature. The ammonia was evaporated and the residuediluted with water (50 ml). The resulting solid was collected, washedwith water and dried to give the title compound (1.24 g, 73%). MH (ES+)m/e 171 [M+H]⁺.

Step 2. 2-Chloro-4-methoxy-5-nitropyridine

A stirred solution of phosphorous oxychloride (8 ml) andN,N-diethylaniline (1.9 ml, 12 mmol) at 0° C. was treated with theproduct of Step 1 (1.7 g, 10 mmol). The mixture was heated at reflux for3 hours and then cooled to room temperature. The mixture was evaporatedin vacuo and the residue co-evaporated with toluene. The residue wasadded to ice-water and the solution extracted with ethyl acetate. Theorganic phase was dried and evaporated in vacuo to give the titlecompound (1.78 g, 94%). ¹H NMR (CDCl₃) 8.82 (1H, s), 7.05 (1H, s), 4.06(3H, s).

Step 3. 2,4-Dimethoxy-5-nitropyridine

A solution of the product of Step 2 (950 mg, 5 mmol), sodium methoxide(695 mg, 12.5 mmol) in methanol (10 ml) was heated at reflux for 2hours. After cooling the solvent was removed in vacuo and the residuepartitioned between ethyl acetate and water. The organic phase waswashed with water and brine, dried and evaporated in vacuo to give thetitle compound (900 mg, 98%). MS (ES+) m/e 185 [M+H]⁺.

Step 4.4-(1-Cyclopropyl-6-methoxy-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

The title compound was prepared from the product of Step 3 using themethods described in Example 2 Step 1, followed by Example 1 Steps 2-4;MS (AP+) m/e 273 [M+H]⁺.

EXAMPLE 2964-(1-Ethyl-6-methoxy-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

The title compound was prepared from the product of Example 295, Step 3and ethylamine using the methods described in Example 2, Step 1 followedby Example 1, Steps 2-4; MS (ES+) m/e=261 [M+H]⁺.

EXAMPLE 2974-(1-Cyclopropyl-6-phenoxy-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

Step 1. 4-Methoxy-5-nitro-2-phenoxypyridine

A solution of phenol (226 mg, 2.4 mmol) in N,N-dimethylformamide (5 ml)was treated with sodium hydride (144 mg, 60% dispersion in oil, 2.4mmol). After stirring at room temperatures for 10 minutes the suspensionwas added to a solution of the product of Example 295 Step 2 (377 mg, 2mmol) in N,N-dimethylformamide (2 ml). After 2 hours saturated ammoniumchloride solution was added and the solution was extracted with ethylacetate. The organic phase was washed with water and brine, dried andconcentrated in vacuo to give the title compound which was used directlyin subsequent steps. MS (AP+) m/e 247 [M+H]⁺.

Step 2.4-(1-Cyclopropyl-6-phenoxy-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

The title compound was prepared from the product of Step 1 using themethods described in Example 2 Step 1, followed by Example 1 Steps 24;MS (AP+) m/e 335 [M+H]⁺.

EXAMPLE 2984-(1-Ethyl-6-phenoxy-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

Step 1. 2-Chloro-4-(ethylamino)-5-nitropyridine

A solution of 4-(ethylamino)-2-methoxy-5-nitropyridine (5.0 g, 25.3mmol) in POCl₃ (25 mL) was heated to 100° C. in a sealed tube for 1week. The reaction mixture was cooled and concentrated and the residuewas taken up in EtOAc/H₂O and carefully quenched with sat. K₂CO₃. Theaqueous layer was extracted with EtOAc, washed with H₂O, dried (MgSO₄)and concentrated to give an orange oil which solidified on standingwhich was used without further purification. MS (ES+) m/e 202 [M+H]⁺.

Step 2. 4-(Ethylamino)-5-nitro-2-phenoxypyridine

A solution of sodium phenoxide (prepared from phenol and NaH) (6 mmol)in THF (3 mL) was added to a solution of the product from Step 1 (600mg, 3.0 mmol) in THF (2 mL) and the resulting solution was heated toreflux overnight. The solution was cooled, poured into H₂O and extractedwith EtOAc. The organic layers were washed with H₂O and brine, dried,filtered and concentrated to give a residue which was purified by columnchromatography (5-80% EtOAc in hex) to give the title compound which wasused directly in the next step. MS (ES+) m/e 260. [M+H]⁺.

Step 3.4-(1-Ethyl-6-phenoxy-1H-imidazo[4,5-c]pyridin-2-yl)furazan-3-ylamine

The title compound was prepared from the product of Step 2 using themethods described in Example 1 Steps 2-4; MS (ES+) m/e 323 [M+H]⁺.

The following compounds were prepared from the product of Example 298,Step 1, by the method of Example 298 Steps 2-3.

Example Phenol Characterisation 299 4-(1-Ethyl-6- 4-fluorophenol MS(ES+) m/e (4-fluorophenoxy)-1H- 341 [M + H]⁺ imidazo[4,5- c]pyridin-2-yl)furazan-3-ylamine 300 N-(3-{[2-(4- 3-acetamidophenol MS (ES+) m/efurzan-3-yl)-1- 380 [M + H]⁺ ethyl-1H-imidazo[4,5- c]pyridin-6-yl]oxy}phenyl)acetamide hydrochloride 301 N-(4-{[2-(4- 4-acetamidophenolMS (ES+) m/e furazan-3-yl)- 380 [M + H]⁺ 1-ethyl-1H- imidazo[4,5-c]pyridin-6- yl]oxy}phenyl)acetamide hydrochloride

EXAMPLE 3022-(4-amino-furazan-3-yl)-1-ethyl-N-phenyl-1H-imidazo[4,5-c]pyridin-6-amine

Step 1. 4-(Ethylamino)-5-nitro-2-(phenylamino)pyridine

Anline (1.4 mL, 15 mmol) was added to the product from Example 298, Step1 (600 mg, 3.0 mmol) in THF (5 mL) and heated to reflux overnight. Thesolution was cooled, poured into H₂O and extracted with EtOAc. Theorganic layers were washed with H₂O and brine, dried, filter andconcentrated to give a residue which was purified by columnchromatography (20-100% EtOAc in hex) to give the title compound whichwas used directly in the next step. MS (ES+) m/e 259. [M+H]⁺.

Step 2.2-(4-Amino-furazan-3-yl)-1-ethyl-N-phenyl-1H-imidazo[4,5-c]pyridin-6-amine

The title compound was prepared from the product of Step 1 using themethods described in Example 1 Steps 24; MS (ES+) m/e 322 [M+H]⁺.

EXAMPLE 3034-(1-Ethyl-6-methylsulfanyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

Step 1. Ethyl-(2-methylsulfanyl-5-nitro-pyridin-4-yl)-amine

Sodium methyl thiolate (308 mg, 4.4 mmol) was added to a solution of theproduct from Example 298, Step 1 (800 mg, 4.0 mmol) in DMF (20 mL).After 5 min the reaction mixture was poured into H₂O and extracted withEtOAc. The organic layers were washed with H₂O and brine, dried,filtered and concentrated to give an oil which solidified on standingand was used without further purification. MS (ES+) m/e 214. [M+H]⁺.

Step 2. N-4-ethyl-6-methylsulfanyl-pyridine-3,4-diamine

The title compound was prepared from the product of Step 1 using themethod of Example 177 Step 4. MS (ES+) m/e 184. [M+H]⁺.

Step 3.4-(1-Ethyl-6-methylsulfanyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

The title compound was prepared from the product of Step 2 using themethod of Example 1, Steps 3-4. MS (ES+) m/e 277. [M+H]⁺.

EXAMPLE 3044-[1-[4-(2-Dimethylamino-ethoxy)-phenyl]-6-(4-fluorophenoxy)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

Step 1. (2-Chloro-5-nitro-pyridin-4-yl)-(4-methoxyphenyl)-amine

Anisole (908 mg, 7.4 mmol) was added to a solution of2,4-dichloro-5-nitropyridine (1.30 g, 6.7 mmol) and triethylamine (1.02mL, 7.4 mmol) in THF (5 mL). The mixture was allowed to stir at rt for 1h, then was poured into H₂O and extracted with EtOAc. The organic layerswere washed with H₂O and brine, dried, filtered and concentrated to aresidue which was purified by column chromatography (5-50% EtOAc in hex)to give the title compound as an orange solid, 1.46 g (78%). MS (ES+)m/e 280 [M+H]⁺.

Step 2.4-[1-[4-(2-Dimethylamino-ethoxy)-phenyl]-6-(4-fluorophenoxy)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

The title compound was prepared starting from the product of Step 1 bythe method of Example 299, followed by the method of Example 38,followed by the method of Example 41. MS (ES+) m/e 476. [M+H]⁺.

EXAMPLE 3054-(1-Cyclopropyl-6-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

The title compound was prepared from2,4-dichloro-6-methyl-3-nitropyridine (R. J. Chorvat et al., J. Med.Chem., 1999, 42, 833-848) using the methods in Example 2 Step 1,followed by Example 1 Steps 24; MS (ES+) m/e 257 [M+H]⁺.

EXAMPLE 3064-(1-Cyclopropyl-6-methyl-5-oxy-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

A solution of the product of Example 305 (256 mg, 1 mmol) andmeta-chloroperbenzoic acid (50%, 414 mg, 1.2 mmol) in dichloromethane(10 ml) was stirred at room temperature for 1 hour. The solution wasdiluted with dichloromethane and the organic solution washed withaqueous sodium thiosulphate, saturated sodium bicarbonate solution,water and brine, dried and concentrated in vacuo to give the titlecompound (242 mg, 89%). MS (ES+) m/e 273 [M+H]⁺.

EXAMPLE 3074-(9-Cyclopropyl-2-methylsulfanyl-9H-purin-8-yl)-furazan-3-ylamine

Step 1.(6-Chloro-2-methylsulfanyl-5-nitro-pyrimidine-4-yl)-cyclopropyl-amine4,6-Dichloro-5-methylsulfanyl-5-nitro-pyrimidine (PCT Int. Appl. (2003),WO 0302544 (14.1 g, 59 mmol), and triethylamine (8.2 ml, 59 mmol) weredissolved in ethanol (400 ml) containing tetrahydrofuran (50 ml) at −60°C. Cycloproplyamine (4.06 ml, 59 mmol) was added dropwise maintaining aninternal temperature of −60° C. and stirred slowly to room temperatureover 3 hours. The solution was concentrated in vacuo and the residueslurried in diethyl ether. Solid triethylamine hydrochloride wasfiltered, washed with diethyl ether and the filtrate concentrated invacuo to afford a crude solid. The solid was purified by columnchromatography eluting with a gradient of 40% dichloromethane in hexaneto dichloromethane, to afford the title compound (17.89 g, 97%); MS(ES+) m/e 260/262 [M+H]⁺.Step 2. 6-chloro-N4-cyclopropyl-2-methansulfanyl-pyrimidine-4,5-diamine

The product of step 1 (5.21 g, 20 mmol) was dissolved in ethanol (150ml) containing tetrahydrofuran (150 ml) and hydrogenated at 1 atmospherefor 5 hours at room temperature over 10% palladium on charcaol. Thecatalyst was filtered and the filtrate concentrated in vacuo to affordthe title product (4.02 g 87%) that was used in the next step withoutfurther purification; MS (ES+) m/e 231/233 [M+H]⁺.

Step 3.(6-Chloro-9-cyclopropyl-2-methylsulfanyl)-9H-purin-8-yl)-acetonitrile

The title product was obtained from product of step 2 using an analogousprocedure to that used in example 1 step 3; MS (ES+) m/e 279/281 [M+H]⁺.

Step 4. (9-Cyclopropyl-2-methylsulfanyl-9H-purin-8-yl)-acetonitrile

The product of step 3 (81 mg, 0.3 mmol) and zinc powder (300 mg, 4.6mmol) were heated at reflux in 3N ammonium chloride solution (10 ml) andtoluene (5 ml) for 48 hours. The crude mixture was filtered throughcelite and the filtrate extracted with ethyl acetate (×3). The combinedextracts were washed with water (×3), brine, dried over anhydrousmagnesium sulfate and concentrated in vacuo to afford a crude solid. Thesolid was purified by column chromatography eluting with a gradient ofhexane to ethyl acetate to afford the title compound (50 mg, 68%); ¹HNMR (CDCl₃) 8.87 (1H s), 4.15 (2H, s), 3.29 (1H, m), 2.65 (3H, s), 1.34(4H, m).

Step 5.4-(9-Cyclopropyl-2-methylsulfanyl-9H-purin-8-yl)-furazan-3-ylamine

The title compound was prepared from the product of step 4 using ananalogous procedure to that used in example 1 step 4; MS (ES+) m/e 290[M+H]⁺.

EXAMPLE 308 3-(1-Ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-pyrazin-2-ylamine

To polyphosphoric acid, preheated to 130° C., was added in one portionan intimate mixture of the product of Example 1 Step 2 (206 mg, 1.5mmol) and 3-aminopyrazine-2-carboxylic acid (230 mg, 1.65 mmol). Thetemperature was increased to 195° C. for 1 hour and then cooled back to130° C. for a further 1 hour. The viscous oil was poured on to icecontaining saturated sodium carbonate solution and diethyl ether (5 ml)and the aqueous solution was extracted with chloroform (×5). Thecombined organic extracts were washed with brine, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The crude solid waspurified by silica gel chromatography eluting with a gradient ofdichloromethane to 0.880 ammonia:ethanol:dichloromethane (1:9:40), toafford the title compound, (20 mg, 6%); MS (ES+) m/e 241 [M+H]⁺.

EXAMPLE 3094-(1-Ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazol-3-ylamine

Step 1.Dimethylamino-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-acrylonitrile

The product of Example 1 Step 3 (334 mg, 1.8 mmol) andN,N-dimethylformamide dimethylacetal (214 mg, 1.8 mmol) in orthoxylene(4 ml) was heated under reflux for 45 min. After cooling, the solutionwas concentrated and the residue co-evaporated with toluene (×3) toafford the title compound which was used directly in the next step; MS(ES+) m/e 242 (M+H)⁺.

Step 2. 4-(1-Ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazol-3-ylamine

The product of Step 2 (217 mg, 0.9 mmol) and hydrazine hydrate (90 mg,1.8 mmol) in methanol (5 ml) was heated under reflux for 5 hours. Aftercooling, the reaction mixture was concentrated and the residue purifiedby silica gel chromatography eluting with 0.880ammonia:ethanol:dichloromethane (1:9:90), to afford the title compound,(27 mg, 13%); MS (ES+) m/e 229 [M+H]⁺.

EXAMPLE 3102-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridine-7-carbaldehyde

A solution of the product from Example 100 (0.1 g, 0.324 mmol) intetrahydrofuran (4 ml) at −78° C. was treated with a i 0.6M solution ofn-butyllithium (0.6 ml, 0.97 mmol) in hexanes. After 5 minutes themixture was treated with dimethylformamide (0.3 ml) and allowed to reachroom temperature. After 30 minutes at room temperature the reaction wascarefully quenched with water and extracted into dichloromethane (×2).The organic layer was then washed with brine, dried (Na₂SO₄) and reducedin vacuo. The residue was purified by silica gel chromatography elutingwith ethyl acetate, to afford the title compound, (0.0349, 41%); MS(ES+) m/e 259 [M+H]⁺.

EXAMPLE 311[2-(4-Amino-furazan-3-yl)-3-ethyl-3H-imidazo[4,5-c]pyridin-4-yl]-methanol

A solution of the product from Example 310 (0.150 g, 0.577 mmol) inmethanol (10 ml) was treated with sodium borohydride (0.0249, 0.635mmol) and stirred at room temperature for 1 hour. The mixture was thentreated with a few drops of acetic acid and then applied directly to anSCX ion exchange cartridge and washed with methanol and then a mixtureof 0.880 ammonia and methanol (1:9).

The basic fractions were combined and reduced to furnish the titlecompound without further purification; MS (ES+) m/e 263 [M+H]⁺.

EXAMPLE 312[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-[1-(2-methoxy-ethyl)-piperidin-4-yl]-amine

Step 1. 1-(2-methoxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butylester

A mixture of piperidin-4-yl]-carbamic acid tert-butyl ester (500 mg, 2.5mmol), potassium carbonate (621 mg, 4.5 mmol) and1-bromo-2-methoxyethane (382 mg, 2.75 mmol) in ethanol 5 ml) was heatedat reflux for 18 hours. After cooling to room temperature the mixturewas filtered and the filtrate concentrated in vacuo. Purification of theresidue by silica gel chromatography elutingdichloromethane/methanol/0.880 ammonia (100:10:1) gave the titlecompound (500 mg, 78%); MS (ES+) m/e 259 [M+H]⁺.

Step 2. 1-(2-Methoxy-ethyl)-piperidin-4-ylamine

The title compound was prepared from the product of Step 1 using themethod of Example 21; (165 mg, 54%); MS (ES+) m/e 159 [M+H]⁺.

Step 3.[2-(4-Amino-furazan-3-yl)-1-ethyl-1H-imidazo[4,5-c]pyridin-7-ylmethyl]-[1-(2-methoxy-ethyl)-piperidin-4-yl]-amine

The title compound was prepared from the product of Step 2 the productof Example 310 using the method of Example 149; MS (ES+) m/e 401 [M+H]⁺.

EXAMPLE 313 4-(3-ethyl-3H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

Step 1. Ethyl-(4-nitro-1-oxy-pyridin-3-yl)-amine

A solution of 3-bromo-4-nitropyrimidine-1-oxide (Daisley, R. W.,Hanbali, J. R.; Org. Prep. Proced. Int., 1983, 15(4), 280) (8.1 g, 37mmol) in chloroform (250 ml) at 0° C. was treated with ethylamine (70%aqueous solution, 25 ml). After stirring at room temperature for 3 hoursadditional ethylamine solution (25 ml) was added and stirring continuedfor a further 3 hours. The solution was concentrated in vacuo and theresidue was purified by silica gel chromatography, eluting with agradient of 10% ethylacetate/hexane to ethylacetate to afford the titlecompound, (3.68 g, 54%); ¹H NMR (CDCl₃) 8.02 (1H, d, J=7.6 Hz), 7.92(1H, d, J=1.6 Hz), 7.81 (1H, br s), 7.46 (1H, dd, J=7.6, 1.6 Hz), 3.32(2H, m), 1.40 (3H, t, J=7.2 Hz).

Step 2. N-3-ethyl-pyridine-3,4-diamine

The product of step 1 (3.68 g, 20 mmol) was dissolved in a 1:1 mixtureof ethanol:tetrahydrofuran (300 ml) and hydrogenated at room temperatureand atmospheric pressure using raney nickel (ca. 1 g) for 18 hours. Thecatalyst was removed by filtration on a filter aid pad and the filtrateconcentrated in vacuo to afford the title compound which was usedwithout further purification, (2.72 g, 99%); ¹H NMR (DMSO) 7.53 (2H, m),6.43 (1H, d, J=4.8 Hz), 5.50 (2H, br s), 4.42 (1H, br s), 3.01 (2H, m),1.21 (3H, t, J=7.2 Hz).

Step 3. 3-ethyl-3H-imidazo[4,5-c]pyridin-2-yl)-acetonitrile

The title compound was prepared from the product of step 2 using theanalogous procedure to that used in example 1, step 3, (1.56 g, 11mmol), affording (1.099, 49%); ¹H NMR (CDCl₃) 8.88 (1H d, J=0.8 Hz),8.49 (1H, d, J=5.6 Hz), 7.68 (1H, dd, J 5.6, 0.8 Hz), 4.38 (2H, q, J 7.4Hz), 4.13 (2H, s), 1.59 (3H, t, J=7.4 Hz).

Step 4. 4-(3-ethyl-3H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

The title compound was prepared from the product of step 2 using theanalogous procedure to that used in example 1, step 4, (1.03 g, 5.5mmol) affording (240 mg, 49%); MS (ES+) m/e 231 [M+H]⁺.

EXAMPLE 3144-(3-Ethyl-5-oxy-3H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

The product of Example 313, Step 4 (362 mg, 1.6 mmol) in acetic acid (2ml) was treated with 30% wt aqueous solution of hydrogen peroxide (432mg, 3.1 mmol) and the solution was heated at 80° C. for 18 hours. Aftercooling to room temperature the mixture was basified with solid sodiumcarbonate and extracted with chloroform (×5). The combined extracts werewashed with brine, dried over anhydrous sodium sulfate and concentratedin vacuo. The residue was purified by column chromatography eluting with0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the titleproduct, (370 mg, 96%); MS (ES+) m/e 247 [M+H]⁺.

EXAMPLE 3154-(3-ethyl-4-methoxy-3H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-ylamine

The product of Example 314 (370 mg, 1.5 mmol) in phosphorous oxychloride(5 ml). was heated at reflux for 4 hours. The solution was cooled andco-evaporated with toluene, the residue was basified with ice coldsodium carbonate and the aqueous solution extracted with ethyl acetate(×3). The combined extracts were washed with brine, dried over anhydroussodium sulfate and concentrated in vacuo. The residue was suspended in asolution of 50% sodium hydroxide (5 ml), containing methanol (5 ml) andheated at 80° C. for 5 hours. The solution was concentrated in vacuo andthe resulting wet solid that was extracted with ethyl acetate (×3). Thecombined extracts were washed with water (×2), brine, dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by column chromatography eluting with a gradient ofdichloromethane to 0.880 ammonia:ethanol:dichlorormethane (1:9:90), toafford the title compound (30 mg, 8%); MS (ES+) m/e 445 [M+H]⁺.

EXAMPLE 3164-[1-(2-Methanesulfonyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine

To a 0° C. solution containing 19 mg of example 97 (0.05 mmols) in 0.5mL of dry DMF and 0.22 mL of triethylamine, was added 7 mg ofmethanesulfonyl chloride (0.06 mmols). The reaction mixture turnedyellow. After stirring at 0° C. for 30 min., the reaction mixture waspartitioned between 5 mL water and 10 mL of EtOAc. The organic layer waswashed with water (2×5 mL), dried over MgSO₄, filtered, and concentratedin vacuo. The resulting residue was purified by Gilson reverse-phaseHPLC to yield the title compound (3 mg, 14%). MS (ES+) m/e 412 [M+H]⁺.

PHARMACY EXAMPLES

Tablets

a)

Compound of the invention 50.0 mg Lactose 70.0 mg MicrocrystallineCellulose 70.0 mg Cross-linked Polyvinylpyrrolidone 8.0 mg MagnesiumStearate 2.0 mg Compression weight 200.0 mg

The compound of the invention, microcrystalline cellulose, lactose andcross-linked polyvinylpyrrolidone are sieved through a 500 micron sieveand blended in a suitable mixer. The magnesium stearate is sievedthrough a 250 micron sieve and blended with the active blend. The blendis compressed into tablets using suitable punches.

b)

Compound of the invention 50.0 mg Lactose 120.0 mg Pregelatinised Starch20.0 mg Cross-linked Polyvinylpyrrolidone 8.0 mg Magnesium Stearate 2.0mg Compression weight 200.0 mg

The compound of the invention, lactose and pregelatinised starch areblended together and granulated with water. The wet mass is dried andmilled. The magnesium stearate and cross-linked polyvinylpyrrolidone arescreened through a 250 micron sieve and blended with the granule. Theresultant blend is compressed using suitable tablet punches.

Capsules

a)

Compound of the invention 50.0 mg Lactose 148.0 mg Magnesium Stearate2.0 mg Fill weight 200.0 mg

The compound of the invention and pregelatinised starch are screenedthrough a 500 micron mesh sieve, blended together and lubricated withmagnesium stearate, (meshed. through a 250 micron sieve). The blend isfilled into hard gelatine capsules of a suitable size.

b)

Compound of the invention 50.0 mg Lactose 132.0 mg Polyvinylpyrrolidone8.0 mg Cross-linked Polyvinylpyrrolidone 8.0 mg Magnesium Stearate 2.0mg Fill weight 200.0 mg

The compound of the invention and lactose are blended together andgranulated with a solution of polyvinylpyrrolidone. The wet mass isdried and milled. The magnesium stearate and cross-linkedpolyvinylpyrrolidone are screened through a 250 micron sieve and blendedwith the granules. The resultant blend is filled into hard gelatinecapsules of a suitable size.

Injection Formulation

% w/v Compound of the invention 0.10 Water for injections B.P. to 100.00

Sodium chloride may be added to adjust the tonicity of the solution andthe pH may be adjusted to that of maximum stability and/or to facilitatesolution of the compound of the invention using dilute acid or alkali orby the addition of suitable buffer salts. Solubilisers, such ascosolvents, may also be added to facilitate solution of the compound ofthe invention. Antioxidants and metal chelating salts may also beincluded. The solution is clarified, made up to final volume with waterand the pH remeasured and adjusted if necessary, to provide 1 mg/ml ofthe compound of formula (I).

The solution may be packaged for injection, for example by filling andsealing in ampoules, vials or syringes. The ampoules, vials or syringesmay be aseptically filled (e.g. the solution may be sterilised byfiltration and filled into sterile ampoules under aseptic conditions)and/or terminally sterilised (e.g. by heating in an autoclave using oneof the acceptable cycles). The solution may be packed under an inertatmosphere of nitrogen.

Preferably the solution is filled into ampoules, sealed by fusion of theglass and terminally sterilised.

Further sterile formulations are prepared in a similar manner containing0.05, 0.20 and 0.5% w/v of the compound of the invention, so as toprovide respectively 0.5, 2 and 5 mg/ml of the compound of theinvention.

Biological Activity

Rho-kinase Activity

Using the test procedure described in the specification the compounds ofthe examples where found to have a pIC50 in the range 9 to 5.2.

Msk-1 Activity

The compounds of the examples have a pIC50 value in the range of 9.28 to5.15.

The compounds of the invention are essential non-toxic attherapeutically useful doses. Thus no adverse effects were observed whencompounds of the invention have been administered to rats at a dose of10 mg/kg.

1. A compound of the general formula (I)

and physiologically acceptable salts and or N-oxides thereof wherein, X³is N, X⁴ is CR⁶, X¹ is CR₃, and X² is CR⁴; R¹ is a group C

wherein X₉ is O and X₁₀ is N; R₂ represents hydrogen, hydroxy, aryl,heteroaryl, C₃₋₇cycloalkyl, heterocyclyl, a group YR₁₂, N═R₁₃,CONR₁₄R₁₅, COCH₂NR₁₉R₂₀, NR₁₄COR₁₆, SO₂NR₁₄R₁₅ or C₁₋₆alkyl [optionallysubstituted by a group selected from optionally substituted phenyl,C₃₋₇cycloalkyl, heteroaryl, heterocyclyl, acylamino, NH₂, R₁₉NH,R₁₉R₂₀N, SO₂NR₁₄R₁₅, CONR₁₄R₁₅, NR₁₄COR₁₆, OalkNR₁₉R₂₀, SalkNR₁₉R₂₀orNR₁₇SO₂R₁₈ group]; R₃, R₄, and R₆, independently represent a groupselected from hydrogen, halogen, hydroxy, R₁₉O, R₁₉S(O)_(n), NH_(2,)R₁₉NH, R₁₉R₂₀N, nitro, formyl, C1-4alkanoyl, alkenyl (optionallysubstituted by optionally substituted phenyl, heterocyclyl, orheteoaryl), carboxy, optionally substituted phenyl, heteroaryl,cycloalkyl, cycloalkylalkyl, aryloxy, heteroaryloxy, heterocyclyl,CONR₁₄R₁₅, NR₁₄COR₁₆ SO₂NR₁₄R₁₅, NR₁₇SO₂R₁₈ or C₁₋₆alkyl [optionallysubstituted by a group selected from optionally substituted phenyl,C₃₋₇cycloalkyl, heteroaryl, heterocyclyl, NH₂, R₁₉NH, R₁₉R₂₀N,acylamino, hydroxy, CONR₁₄R₁₆, NR₁₄COR₁₆, SO₂NR₁₄R₁₅, NR₁₇SO₂R₁₈,OalkNR₁₉R₂₀, or SalkNR₁₉R₂₀group]; R₁₉ and R₂₀ independently represent agroup selected from C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylalkyl,aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl orheterocyclylalkyl; Y represents O, NH, NR₁₂ or S(O)_(n); R₁₂ representsaryl, heteroaryl, cycloalkyl, heterocyclyl or C₁₋₆alkyl [optionallysubstituted by a group selected from optionally substituted phenyl,C₃₋₇cycloalkyl, heteroaryl, heterocyclyl, NH₂, R₁₉NH, R₁₉R₂₀N ,acylamino, hydroxy, CONR₁₄R₁₅, NR₁₄COR₁₆, SO₂NR₁₄R₁₅,NR₁₇SO₂R₁₈OalkNR₁₉R₂₀, or SalkNR19R₂₀ group]; R₁₃ represents analkylidene group which may be substituted by an aryl, heteroaryl,heterocyclyl or cycloalkyl group or R₁₃ represents a cycloalkylidene orheterocycloalkylidene group; R₁₄ and R₁₅ independently representhydrogen, aryl, heteroaryl, cycloalkyl or C₁₋₆alkyl [optionallysubstituted by a group selected from optionally substituted phenyl,C₃₋₇cycloalkyl, heteroaryl, heterocyclyl, NH₂, R₁₉NH, R₁₉R₂₀N , oracylamino group] or R₁₄ and R₁₅ together with the nitrogen atom to whichthey are attached form a 4-7 heterocyclic ring which may be saturated orunsaturated and optionally contains another heteroatom selected from O,N or S(O)_(n); R₁₆ and R₁₈ independently represent, aryl, heteroaryl,heterocyclyl, cycloalkyl or C₁₋₆alkyl [optionally substituted by a groupselected from optionally substituted phenyl, C₃₋₇cycloalkyl, heteroaryl,heterocyclyl, NH₂, R₁₉NH, R₁₉R₂₀N , or acylamino group] or the groupNR₁₄R₁₅ wherein R₁₄ and R₁₅ have the meanings defined above; R₁₇represents hydrogen, aryl, heteroaryl, heterocyclyl, cycloalkyl orC₁₋₆alkyl [optionally substituted by a group selected from optionallysubstituted phenyl, C₃₋₇cycloalkyl, heteroaryl, heterocyclyl, NH₂,R₁₉NH, R₁₉R₂₀N , or acylamino group]; Alk is a C₂₋₄ straight or branchedalkylene chain n is zero, 1 or
 2. 2. A compound as claimed in claim 1wherein R₂ represents hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylmethyl, phenyl or phenyl substituted by (amino,dialkylamino, dialkylaminoalkylamino, alkyl, alkanoyl, alkoxy, halo,hydroxy, aminoalkyl, hydroxalkoxy, aminoalkoxy, alkylaminoalkoxy,N-aralkyl-Nalkylaminoalkoxy, aminocarbonylalkoxy,alkylaminocarbonylalkoxy, dialkylaminocarbonylalkoxy, ureidoalkoxy,alkylureido, dialkylamino-acetamido, alkylthioalkoxy, phenylthioalkoxy,alklsulphinylalkoxy, phenylsulphinylalkoxy, alkylsulphonylalkoxy,phenylsulphonylalkoxy, cyanoalkoxy, acylaminoethoxy,alkylsuphonylaminoalkoxy, phenylsulphonylaminoalkoxy,alkoxycarbonylalkoxy, heterocyclylalkoxy, heterocyclyloxy,heterocyclyl), alkyl substituted by (hydroxy, amino, acylamino, R₁₉NH,R₁₉R₂₀N, a 4-7-membered heterocyclyl group), a 4-7 membered heterocyclylgroup, a 5,6 fused bicyclic hetroaryl group, a 6,6 fusedbicyclicheterocyclic group, a 6,5 fused heterocyclic group or a 6,7fused heterocyclic group.
 3. A compound as claimed in claim 1 wherein R₂represents hydrogen, methyl, ethyl, isopropyl, sec butyl, 2-ethylbutyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopropylmethyl, cyclohexylmethyl, phenyl, phenyl substituted by[amino 4-dimethylamino, dimethylaminoethylamino, N-methyldimethylaminoethylamino, N,N-bis(2-dimethylaminoethyl)amino), ethyl,acetyl, methoxy 3-methylbutoxy, chlorine, brominehydroxy, aminomethyl,2-hydroxyethoxy, 3-hydroxypropoxy, 2-aminoethoxy, 2-methylaminoethoxy,2-dimethylaminoethoxy, 2-diethylaminoethoxy,2-diethylamino-1-methylethoxy, 2-disopropylamino-1-methylethoxy,N,N-benzyl N-methylaminoethoxy, aminocarbonylmethoxy,aminocarbonyl-2-methylethoxy, aminocarbonylethoxy,methylaminocarbonylmethoxy, dimethylaminocarboxymethoxy, ureidomethoxy,3-methylureido, dimethylaminoacetamido, methylthiomethoxy,phenylthiomethoxy, methylsulphinylmethoxy, phenylsulphinylmethoxy,methylsulphonylmethoxy, phenylsulphonylmethoxy, cyanomethoxy,2-cyanoethoxy, t-butoxycarbonylaminoethoxy, isoxazolylaminoethoxy,isonicotinylaminoethoxy, methylsulphonylaminoethoxy,phenylsulphonylaminoethoxy, 2-methoxycarbonyl 1-methylethoxy,morpholinoethoxy, piperidinoethoxy, 1-pyrroldino-2-ylmethoxy,1-methyl-piperidino-4-yloxy or 3-pyrrolidinyl,]2-hydroxy-1-methyl-ethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl,4-butyloxycarbonylamino-butyl, 2-dimethylamino-1-methylethyl,4-diethylamino-1-methyl-butyl, 3-dimethylaminopropyl,4-methylpiperazin-1-ethyl, 2-piperazin-yl-ethyl, piperidine 4-yl methyl,piperidine 3-yl methyl, piperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl,5-indazolyl or 6-indazolyl, tetrahydroisoquinolin-5-yl, 2-methyltetrahydroisoquinolin-7-yl,2-methanesulphonyl-tetrahydroisoquinolin-7-yl,tetrahydroisoquinolin-7-yl, 3,4-dihydro-2H-isoquinolin-1-one-7-yl,2,3-dihydro-1H-isoindol-5-yl, benzo{1,3]dioxol-5-yl or2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl.
 4. A compound as claimed inclaim 1 wherein R₃ represents hydrogen, halogen, hydroxy, carboxyl,phenyl or phenyl (substituted by one or two groups selected from alkoxy,hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, amino,acetamido, aminoalkyl, alkyl, carboxyl carboxamido,N,N-dimethylcarboxamido, cyano, formyl, phenoxy, CH₃S(O)n wherein n iszero, 1 or 2, CH₃SO₂NH, or halogen), or heterocyclyl, heteroaryl,6,5-fused bicycloheterocyclyl, an optionally substituted phenylsubstituted by the group CH₂NR₁₉R₂₀ wherein R₁₉ is alkyl, phenyl or aheterocyclic group and R₂₀ is hydrogen or methyl, or NR₁₉R₂₀ is a 4-7heterocyclic group, alkyl substituted by (a 4-7 membered heterocyclylgroup or a group NR₁₉R₂₀ (wherein R₁₉ is hydroxylalkyl, optionallysubstituted benzyl, C₃₋₇ cycloalkyl, a heterocyclic group, a 4-7membered heterocycylalkyl or C₃₋₇ cycloalkylalkyl, R₂₀ is hydrogen,methyl or acetyl), 4-heterocyclyoxy, heterocyclylalkyloxy, vinyl(optionally substituted by optionally substituted phenyl), CONR₁₄R₁₅wherein R₁₅ is hydrogen, R₁₄ is benzyl, phenethyl, aminoalkyl, 4-7membered heterocyclyl or 4-7 membered heterocyclylalkyl, or R₁₄ and R₁₅together with the nitrogen atom to which they are attached represent a4-7 membered heterocyclyl group, a group R₁₉S(O)n (wherein n is zero, 1or 2 and R₁₉ is optionally substituted phenyl), or a group R₁₉NH and R₁₉is optionally substitued phenyl or heteroaryl.
 5. A compound as claimedin claim 1 wherein R₃ represents hydrogen, bromine, hydroxy, carboxyl,phenyl or phenyl (substituted by one or two groups selected frommethoxy, ethoxy, hydroxy, hydroxymethyl, trifluoromethyl,trifluoromethoxy, amino, acetamido, aminomethyl, aminoethyl, methyl,ethyl, carboxyl, carboxamido, N,N-dimethylcarboxamido, cyano, formyl,phenoxy, CH₃S(O)n wherein n is zero, 1 or 2, CH₃SO₂NH, or fluorine),5-methyl-1,2,4-oxadiazol-3-yl, 2-thienyl, 4-methylthienyl,5-phenylthienyl, 5-formylthienyl, or 3-thienyl, 2-furanyl, pyridyl suchas 3-pyridyl or 4-pyridyl, 3,5-dimethylisoxazol-4-yl, indolyl or8-quinolinyl, benzothienyl, 5-benzo[1,3]dioxolyl, a phenyl orfluorophenyl substituted by the group CH₂NR₁₉R₂₀ (wherein NR₁₉R₂₀represents ethylamino, dimethylamino, 4-morpholino, pyrrolidino,piperidino, piperidin-4-yl-amino or1-t-butoxycarbonyl-piperdin-4-yl-amino), 3-hydroxypropylamino,4-bromobenzylamino, 4-methoxybenzylamino, 4-piperidinylaminomethyl,N-4-piperidinyl-N-methylaminomethyl,1-t-butyoxycarbonyl-piperidinyl-aminomethyl, 4-aminopiperidinomethyl,1,4-diazepan-1-ylmethyl, piperazinomethyl, 4-methylpiperazinomethyl,4-acetylpiperizin-1-ylmethyl, 4-ethylpiperazinomethyl,4-morpholinomethyl, piperidinomethyl, 4-(methylamino)piperidinomethyl,4-cyclopropylaminopiperidinomethyl, pyrrolidinomethyl,3-dimethylaminopyrrolidinomethyl, 2-hydroxymethylpyrrolidinomethyl,4-ethylpiperazino-methyl, 3-pyrrolidin-1-yl-propylaminomethyl,4-(4-fluorophenyl)piperazinomethyl,3-piperidinyl-1-yl-propylaminomethyl,3-morpholin-4-yl-propylaminomethyl, 3-(4-methylpiperazin-ylpropylaminomethyl, 1-methyl piperidin-4-yl-aminomethyl,4-pyrrolidinocarbonylmethyl-piperazinomethyl,2-pyrrolidin-1-ylmethylpyrrolidinomethyl,2-pyrrolidin-1-yl-ethylaminomethyl, 3-dimethylaminopyrrolidinomethyl,1-methyl-piperidin-4-ylaminomethyl,1-isopropyl-piperidin-4-ylaminomethyl, 3-dimethylaminopyrrolidinomethyl,2-(morpholin-yl-methyl)-pyrrolidinomethyl,3-piperidin-1-yl-propylaminomethyl, 3-morpholin-4-yl-propylaminomethyl,3-(4-methylpiperazin-1-ylpropylaminomethyl,piperidin-1-ylmethylpyrrolidinomethyl, 3,5-dimethylpiperazinomethyl,pyrrolidin-1-ylpiperidinomethyl, pyrrolidino-3-ylaminomethyl,pyrrolidin-2-ylmethylaminomethyl,4-aminomethylcyclohexymethylaminonlethyl, 4-aminocyclohexylaminomethyl,2-piperazin-1-ylethylamoinomethyl, 3-amino-pyrrolidinomethyl,pyrrolidino-2-ylmethylaminomethyl, piperidin-4-ylmethylaminomethyl,4-aminomethylpiperdininomethyl, 4-(cyclopropylaminopiperidinomethyl,3-(piperazino-1-yl)propylaminomethyl,2-(morpholin-4-ylmethyl)pyrrolidinomethyl,2-(piperidin-1-ylmethyl)pyrrolidinomethyl,2-(piperazin-1-ylmethyl)pyrrolidinomethyl, piperidin-4-ylmethyl,N-piperidin-4-yl-acetamidomethyl, piperidin-4-yloxy, orpiperidin-4-ylmethyloxy, 4-methyloxystyryl, CONR₁₄R₁₅ wherein R₁₅ ishydrogen, R₁₄ is benzyl, phenethyl, 3-aminopropyl, 4-aminobutyl,6-aminohexyl, 3 or 4-piperidinyl 1-aminomethylcarbonyl-piperidin-4-yl,3-pyrroldinyl, piperidin-2-ylmethyl or piperidin-4-ylmethyl,morpholin-2-ylmethyl or piperazinoethyl, or R₁₄ and R₁₅ together withthe nitrogen atom to which they are attached represent piperazino,1-methylpiperazino, 4-(2-aminoethyl)piperazino,4-(t-butoxycarbonylaminoethyl)piperazino,4-aminomethylcarbonylpiperazino, 4-aminoethylcarbonylpiperazino,4-1-(aminoethylcarbonylpiperazino,4-(1-methylaminoethylcarbonylpiperazino,4-pyrrolidin-2-yl-carbonylpiperazino, pyrrolidino, 3-aminopyrrolidino,2-methoxycarbonylpyrrolidino, morpholino, 2-(pyrrolidin-1-yl)methylpyrrolidino, a group R₁₉S(O)n wherein n is zero, and R₁₉ is phenyloptionally substituted by methoxy, a group R₁₉NH wherein R₁₉ is phenyl,4-morpholinophenyl or 3-aminopyridyl.
 6. A compound as claimed in claim1 wherein R₄ is hydrogen, methyl, methoxy, methylthio, phenylamino orphenoxy optionally substituted by fluorine or acetamido.
 7. A compoundas claimed in claim 1 wherein R₆ is hydrogen, chlorine, hydroxymethyl,methyl, methoxy, phenyl, 1-pyrrolidinyl or 1-pyrazolyl.
 8. Apharmaceutical formulation comprising a compound according to claim 1 ora pharmaceutically acceptable salt and or an N oxide thereof togetherwith one or more pharmaceutically acceptable excipients and/or carriers.9. The method of inhibiting the kinase Msk-1 which comprises theadministration of a compound according to claim 1 and/or aphysiologically acceptable salt thereof.
 10. The method of inhibitingRho-kinase 1 which comprises the administration of a compound accordingto claim 1 and/or a physiologically acceptable salt thereof.
 11. Themethod of inhibiting Rho-kinase 2 which comprises the administration ofa compound according to claim 1 and/or a physiologically acceptable saltthereof.